Heteroaryl inhibitors of pde4

ABSTRACT

The present invention relates to compounds and methods useful as inhibitors of phosphodiesterase 4 (PDE4) for the treatment or prevention of inflammatory diseases and other diseases involving elevated levels of cytokines and proinflammatory mediators.

This application is a continuation application of U.S. application Ser.No. 16/396,457, filed Apr. 26, 2019, which is a continuation applicationof U.S. application Ser. No. 16/111,700, filed Aug. 24, 2018, now U.S.Pat. No. 10,364,258, which is a continuation application of U.S.application Ser. No. 15/680,842, filed Aug. 18, 2017, now U.S. Pat. No.10,093,686, which is a continuation application of U.S. application Ser.No. 14/938,544, filed Nov. 11, 2015, now U.S. Pat. No. 9,777,024, whichis a divisional application of U.S. application Ser. No. 14/349,688,filed Apr. 4, 2014, now U.S. Pat. No. 9,221,843, which is a nationalphase entry under 35 U.S.C. § 371, and claims the benefit of,International Application No. PCT/US2013/066645, filed Oct. 24, 2013,which claims the benefit of U.S. Provisional Applications No.61/718,285, filed Oct. 25, 2012, No. 61/733,675, filed Dec. 5, 2012, andNo. 61/776,937, filed Mar. 12, 2013, the disclosures of which are herebyincorporated by reference as if written herein in their entireties.

Inventions disclosed herein were made with government support underR43MH091791 and U01NS078034 awarded by the National Institutes ofHealth. The government has certain rights in these inventions.

Disclosed herein are new bicyclic heteroaryl compounds and compositionsand their application as pharmaceuticals for the treatment of disease.Methods of inhibition of phosphodiesterase 4 (PDE4) activity in a humanor animal subject are also provided for the treatment diseases such asinflammatory diseases and other diseases involving elevated levels ofcytokines and proinflammatory mediators.

Chronic inflammation is a multi-factorial disease complicationcharacterized by activation of multiple types of inflammatory cells, forexample cells of lymphoid lineage (including T lymphocytes) and myeloidlineage (including granulocytes, macrophages, and monocytes).Proinflammatory mediators, including cytokines, such as tumor necrosisfactor (TNF) and interleukin-1 (IL-1), are produced by these activatedcells. Accordingly, an agent that suppresses the activation of thesecells, or their production of proinflammatory cytokines, would be usefulin the therapeutic treatment of inflammatory diseases and other diseasesinvolving elevated levels of cytokines.

Cyclic adenosine monophosphate (cAMP) is a second messenger thatmediates the biologic responses of cells to a wide range ofextracellular stimuli. When the appropriate agonist binds to specificcell surface receptors, adenylate cyclase is activated to convertadenosine triphosphate (ATP) to cAMP. It is theorized that the agonistinduced actions of cAMP within the cell are mediated predominately bythe action of cAMP-dependent protein kinases. The intracellular actionsof cAMP are terminated by either a transport of the nucleotide to theoutside of the cell, or by enzymatic cleavage by cyclic nucleotidephosphodiesterases (PDEs), which hydrolyze the 3′-phosphodiester bond toform 5′-adenosine monophosphate (5′-AMP). 5′-AMP is an inactivemetabolite.

The superfamily of PDEs is subdivided into two major classes, class Iand class II, which have no recognizable sequence similarity. Class Iincludes all known mammalian PDEs and is comprised of 11 identifiedfamilies that are products of separate genes. Some PDEs are highlyspecific for hydrolysis of cAMP (PDE4, PDE7, PDE8), some are highlycGMP-specific (PDE5, PDE6, PDE9), and some have mixed specificity (PDE1,PDE2, PDE3, PDE10, PDE11). All of the characterized mammalian PDEs aredimeric, but the importance of the dimeric structure for function ineach of the PDEs is unknown.

The PDE4 subfamily is comprised of 4 members: PDE4A, PDE4B, PDE4C, andPDE4D. These enzymes possess N-terminal regulatory domains thatpresumably mediate dimerization, which results in optimally regulatedPDE activity. In addition, activity is regulated via cAMP-dependentprotein kinase phosphorylation sites in this upstream regulatory domain.PDE4 enzymes are broadly expressed and distributed.

Elevated levels of cAMP in human myeloid and lymphoid lineage cells areassociated with the suppression of cell activation. The intracellularenzyme family of PDEs, therefore, regulates the level of cAMP in cells.PDE4 is a predominant PDE isotype in these cells, and is a majorcontributor to cAMP degradation. Accordingly, the inhibition of PDEfunction would prevent the conversion of cAMP to the inactive metabolite5′-AMP and, consequently, maintain higher cAMP levels, and, accordingly,suppress cell activation.

PDE4 inhibitors have been shown to inhibit production of TNFα andpartially inhibit IL-1β release by monocytes (see Semmler et al., Int.J. Immunopharmacol., 15, pp. 409-413, (1993); Molnar-Kimber et al.,Mediators of Inflammation, 1, pp. 411-417, (1992)). PDE4 inhibitors alsohave been shown to inhibit the production of superoxide radicals fromhuman polymorphonuclear leukocytes (see Verghese et al., J. Mol. Cell.Cardiol., 21 (Suppl. 2), S61 (1989); Nielson et al., J. AllergyImmunol., 86, pp. 801-808, (1990)); to inhibit the release of vasoactiveamines and prostanoids from human basophils (see Peachell et al., J.Immunol., 148, pp. 2503-2510, (1992)); to inhibit respiratory bursts ineosinophils (see Dent et al., J. Pharmacol., 103, pp. 1339-1346,(1991)); and to inhibit the activation of human T-lymphocytes (seeRobicsek et al., Biochem. Pharmacol., 42, pp. 869-877, (1991)).

Inflammatory cell activation and excessive or unregulated cytokine(e.g., TNFα and IL-1β) production are implicated in allergic,autoimmune, and inflammatory diseases and disorders, discussed herein.

Additionally, several properties of TNFα, such as stimulation ofcollagenases, stimulation of angiogenesis in vivo, stimulation of boneresorption, and an ability to increase the adherence of tumor cells toendothelium, are consistent with a role for TNF in the development andmetastatic spread of cancer in the host. TNFα recently has been directlyimplicated in the promotion of growth and metastasis of tumor cells (seeOrosz et al., J. Exp. Med., 177, pp. 1391-1398, (1993)).

Investigators have shown considerable interest in the use of PDE4inhibitors as anti-inflammatory agents. Early evidence indicates thatPDE4 inhibition has beneficial effects on a variety of inflammatorycells such as monocytes, macrophages, T-cells of the Th-1 lineage, andgranulocytes. The synthesis and/or release of many proinflammatorymediators, such as cytokines, lipid mediators, superoxide, and biogenicamines, such as histamine, have been attenuated in these cells by theaction of PDE4 inhibitors. The PDE4 inhibitors also affect othercellular functions including T-cell proliferation, granulocytetransmigration in response to chemotoxic substances, and integrity ofendothelial cell junctions within the vasculature.

The design, synthesis, and screening of various PDE4 inhibitors havebeen reported. Methylxanthines, such as caffeine and theophylline, werethe first PDE inhibitors discovered, but these compounds arenonselective with respect to which PDE is inhibited. The drug rolipram,an antidepressant agent, was one of the first reported specific PDE4inhibitors, with a reported IC₅₀ of about 200 nM with respect toinhibiting recombinant human PDE4.

Investigators have continued to search for PDE4 inhibitors that are moreselective with respect to inhibiting PDE4, that have a lower IC₅₀ thanrolipram, and that avoid the undesirable central nervous system (CNS)side effects, such as retching, vomiting, and sedation, associated withthe administration of rolipram. In addition, several companies are nowundertaking clinical trials of other PDE4 inhibitors. However, problemsrelating to efficacy and adverse side effects, such as emesis andcentral nervous system disturbances, remain unsolved.

Accordingly, compounds that selectively inhibit PDE4, isoforms PDE4B orPDE4D, or a PDE4 isoform containing a UCR1 activating mutation (such asPDE4B1 containing UCR1 activating mutation S133D, PDE4B1*; or PDE4D7containing UCR1 activating mutation S54D, PDE4D7*), and, in certainembodiments, that reduce or eliminate the adverse side effectsassociated with prior PDE4 inhibitors, would be useful in the treatmentof disease, including neurologic and psychological diseases, and in theenhancement of memory and cognition. In addition, selective PDE4inhibitors would be useful in the treatment of diseases that wouldbenefit from elevated cAMP levels or reduced PDE4 function in aparticular target tissue.

Compounds and pharmaceutical compositions, certain of which have beenfound to inhibit PDE4 have been discovered, together with methods ofsynthesizing and using the compounds including methods for the treatmentof PDE4-mediated diseases in a patient by administering the compounds.

Certain compounds disclosed herein may possess useful PDE4 inhibitingactivity, and may be used in the treatment or prophylaxis of a diseaseor condition in which PDE4 plays an active role. Thus, in broad aspect,certain embodiments also provide pharmaceutical compositions comprisingone or more compounds disclosed herein together with a pharmaceuticallyacceptable carrier, as well as methods of making and using the compoundsand compositions. Certain embodiments provide methods for inhibitingPDE4. Other embodiments provide methods for treating a PDE4-mediateddisorder in a patient in need of such treatment, comprisingadministering to said patient a therapeutically effective amount of acompound or composition according to the present invention. Relatedembodiments disclose the use of certain compounds disclosed herein astherapeutic agents, for example, in treating inflammatory diseases andother diseases involving elevated levels of cytokines andproinflammatory mediators. Also provided is the use of certain compoundsdisclosed herein for use in the manufacture of a medicament for thetreatment of a disease or condition ameliorated by the inhibition ofPDE4.

Accordingly, provided herein are compounds of structural Formula I:

or a salt, ester, amide, or prodrug thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, CH₂, C(R₂)₂, S(O)_(n) and CO;    -   X is chosen from CR₁ and N;    -   Z is chosen from C and N;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ is chosen from hydrogen, halogen, lower alkyl, hydroxyl,        trifluoromethyl, OR₂, and N(R₂)₂;    -   each R₂ is independently chosen from hydrogen, hydroxyl, and        lower alkyl;    -   R₃ is chosen from lower alkyl, lower heteroalkyl, lower        haloalkyl, and lower cycloalkyl;    -   R₄ is chosen from:        -   null if Z is N; and        -   hydrogen, lower heteroalkyl, and lower alkyl if Z is C;    -   or R₃ and R₄, together with the atoms to which they are        attached, join to form a 4 to 7 membered cycloalkyl or        heterocycloalkyl, any of which may be optionally substituted;    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, and a carboxylic acid isostere, any of which may be        optionally substituted; and    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula I, Z is C.

In other embodiments of Formula I, Z is N.

In certain embodiments of Formula I, R₁ is hydrogen.

In certain embodiments of Formula I, R₃ and R₄ join to form a 4- to7-membered cycloalkyl or heterocycloalkyl.

In certain embodiments of Formula I, R₃ and R₄ join to form a 5-memberedcycloalkyl or 5- or 6-membered heterocycloalkyl.

In certain embodiments of Formula I,

-   -   R₃ and is chosen from lower alkyl, lower cycloalkyl, and        trifluoromethyl;    -   R₄ is chosen from hydrogen and lower alkyl.

In certain embodiments of Formula I, R₃ and R₄ are each lower alkyl.

In certain embodiments of Formula I:

-   -   R₃ and R₄ are each lower alkyl; and    -   Z is C.

In certain embodiments of Formula I, R₃ and R₄ are each chosen frommethyl and ethyl.

In certain embodiments of Formula I, R₃ is methyl and R₄ is ethyl.

In certain embodiments of Formula I, R₃ is ethyl and R₄ is hydrogen.

In certain embodiments of Formula I, R₃ is trifluoromethyl and R₄ ishydrogen.

In certain embodiments of Formula I, R₃ is cyclopropyl and R₄ ishydrogen.

In certain embodiments of Formula I, the compound has a structure chosenfrom:

In certain embodiments of Formula I, the compound has a structure chosenfrom:

In certain embodiments of Formula I, R₄ is null.

In certain embodiments of Formula I, Y is NH.

In certain embodiments of Formula I, Y is CH₂.

In other embodiments of Formula I, Y is O.

In certain embodiments of Formula I, Y is NR₂.

In certain embodiments of Formula I, X is CR₁.

In certain embodiments of Formula I, X is N.

In certain embodiments of Formula I wherein Z is C, X is N, and R₅ issubstituted phenyl, the phenyl is either substituted in the ortho ormeta position, or, if substituted in the para position, contains atleast one additional substituent.

In certain further embodiments of Formula I, R₁ is chosen from hydrogen,halogen, hydroxyl, and NH₂.

In certain embodiments of Formula I, R₁ is hydrogen.

In certain further embodiments of Formula I:

-   -   R₁ is chosen from lower alkyl, OR₂, and N(R₂)₂; and    -   at least one of R₂ is lower alkyl.

In further embodiments of Formula I, R₂ is chosen from methyl, ethyl,propyl, isopropyl, butyl, and t-butyl.

In certain embodiments of Formula I, R₅ is optionally substituted aryl.

In certain embodiments of Formula I, R₅ is substituted phenyl, which iseither substituted in the ortho or meta position, or, if substituted inthe para position, contains at least one additional substituent.

In further embodiments of Formula I, R₅ is substituted with between oneand four substituents of the form R₈—R₉—(R₁₀)_(p), wherein:

-   -   R₈ is chosen from a bond, lower alkyl, lower alkoxy, amino,        lower alkylamino, and sulfonamide;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, amino, carboxyl,        carboxamido, a carboxylic acid isostere, cyano, and tetrazole;    -   R₁₀ is chosen from null, hydrogen, and lower alkyl; and    -   p is an integer chosen from 0, 1 or 2.

In further embodiments of Formula I, R₉ is a carboxylic acid isosterechosen from tetrazole, oxazole, isoxazole, isothiazole, —SO₃H, —SO₂NHR,—PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R, —NN(R)₂,—C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR, —C(O)NHNHSO₂R,—C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole, acyl sulfonamide,cyclobutenedione, cyclopentenedione, wherein R is hydrogen or a carbonchain or ring or a carbon-linked group, such as an alkyl, alkenyl,alkynyl, cycloalkyl, or aryl group, or a heterocycloalkyl or heteroarylgroup where the bond is to a carbon, any of which may be optionallysubstituted.

In further embodiments of Formula I, R₉ is a carboxylic acid isosterechosen from boronic acid, benzoxaborole, 3,3-dimethylbenzoxaborole,3-hydroxy-cyclopent-2-enone and cyclopentenedione.

In certain embodiments of Formula I, R₅ is heteroaryl.

In further embodiments of Formula I, R₅ is a carboxylic acid isostere.

In other embodiments of Formula I, R₅ is a carboxylic acid isosterechosen from tetrazole, oxazole, isoxazole, isothiazole, —SO₃H, —SO₂NHR,—PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R, —NN(R)₂,—C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR, —C(O)NHNHSO₂R,—C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole, acyl sulfonamide,cyclobutenedione, cyclopentenedione, wherein R is hydrogen or a carbonchain or ring or a carbon-linked group, such as an alkyl, alkenyl,alkynyl, cycloalkyl, or aryl group, or a heterocycloalkyl or heteroarylgroup where the bond is to a carbon, any of which may be optionallysubstituted.

In other embodiments of Formula I, R₅ is chosen from benzoxaborole,3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enone andcyclopentenedione.

In yet further embodiments of Formula I, R₅ is benzoxaborole.

In further embodiments of Formula I, R₅ has the structure

wherein

-   -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and    -   q is an integer from 0 to 3.

In yet further embodiments of Formula I,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In certain embodiments of Formula I, R₆ is chosen from:

-   -   substituted phenyl or naphthyl;    -   substituted monocyclic or bicyclic heteroaryl, having between        four and twelve ring atoms, of which up to six are heteroatoms        chosen from O, S, and N;    -   optionally substituted monocyclic or bicyclic heterocycloalkyl,        having between four and twelve ring atoms, of which up to six        are heteroatoms chosen from O, S, and N; and    -   optionally substituted monocyclic or bicyclic C₃-C₁₀ cycloalkyl.

In further embodiments of Formula I, R₆ is substituted with between oneand four substituents chosen from halogen, hydroxy, lower haloalkyl,lower alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and sulfonyl.

In certain further embodiments of Formula I, R₆ is substituted phenyl ornaphthyl.

In certain further embodiments of Formula I, R₆ is optionallysubstituted monocyclic heteroaryl, having between five and six ringatoms, of which up to four are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula I, R₆ is chosen from thiophene,pyrrole, pyrimidine, oxazole, isoxazole, pyrazole, imidazole, thiazole,isothiazole, pyridine, pyrazine and pyridazine, any of which may beoptionally substituted with between a substituent chosen from halogen,hydroxy, trifluoromethyl, methoxy, trifluoromethoxy, acetyl, amino,cyano, and sulfonyl.

In still further embodiments of Formula I, R₆ is thiophene.

In certain further embodiments of Formula I, R₆ is optionallysubstituted bicyclic heteroaryl, having between eight and nine ringatoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula I, R₆ is chosen from indole,benzoxazole, benzisoxazole, benzothiazole, quinoline, isoquinoline, andcoumarin.

In further embodiments of Formula I, R₆ is optionally substitutedmonocyclic heterocycloalkyl, having between five and seven ring atoms,of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula I, R₆ is chosen from pyrrolidine,furan, morpholine, piperazine, and piperidine.

In further embodiments of Formula I, R₆ is optionally substitutedmonocyclic cycloalkyl having between five and seven ring atoms, andoptionally substituted monocyclic cycloalkoxy having between five andseven ring atoms.

In further embodiments of Formula I, R₆ is optionally substitutedcyclopentyl or optionally substituted cyclopentyloxy.

In further embodiments of Formula I, R₆ is optionally substitutedcyclopentyloxy.

In further embodiments of Formula I, R₆ is chosen from 3-chlorophenyland 5-chloro-2-thienyl.

In certain embodiments of Formula I, Z is C.

In certain embodiments of Formula I, R₃ and R₄ join to form a 4- to7-membered cycloalkyl or heterocycloalkyl, any of which may beoptionally substituted.

In certain embodiments of Formula I:

-   -   R₃ and R₄ join to form a 4- to 7-membered cycloalkyl or        heterocycloalkyl, either of which may be optionally substituted;        and    -   Z is C.

In certain embodiments of Formula I, R₃ and R₄ join to form afive-membered cycloalkyl or heterocycloalkyl, any of which may beoptionally substituted.

In certain embodiments of Formula I, X is CR₁.

In certain embodiments of Formula I, R₁ is hydrogen.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

As used herein, two embodiments are “mutually exclusive” when one isdefined to be something which is different than the other. For example,an embodiment wherein R₃ and R₄ combine to form a cycloalkyl is mutuallyexclusive with an embodiment in which R₃ is ethyl and R₄ is hydrogen.Similarly, an embodiment wherein Y is CH₂ is mutually exclusive with anembodiment wherein Y is NH.

In certain embodiments are provided compounds of structural Formula II:

or a salt, ester, amide, or prodrug thereof, wherein:

-   -   A is a 4- to 7-membered cycloalkyl or heterocycloalkyl, any of        which may be optionally substituted;    -   Y is chosen from O, NH, NR₂, CH₂, C(R₂)₂, S(O)_(n) and CO;    -   X is chosen from CR₁ and N;    -   Z is chosen from C and N;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ is chosen from hydrogen, halogen, lower alkyl, hydroxyl,        trifluoromethyl, OR₂, and N(R₂)₂;    -   each R₂ is independently chosen from hydrogen, hydroxyl, and        lower alkyl;    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted;    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula II, A is a five- to six-memberedcycloalkyl or heterocycloalkyl.

In certain embodiments of Formula II, Y is N.

In certain embodiments of Formula II, X is N.

In certain embodiments of Formula II, X is CR₁.

In certain embodiments of Formula I, R₁ is hydrogen.

In certain embodiments of Formula II, Y is NH.

In certain embodiments of Formula II, Y is CH₂.

In other embodiments of Formula II, Y is O.

In certain embodiments of Formula II, Y is NR₂.

In certain embodiments of Formula II, R₅ is optionally substituted aryl.

In certain embodiments of Formula II, R₅ is substituted phenyl, which iseither substituted in the ortho or meta position, or, if substituted inthe para position, contains at least one additional substituent.

In further embodiments of Formula II, R₅ is substituted with between oneand four substituents of the form R₈—R₉—(R₁₀)_(p), wherein:

-   -   R₈ is chosen from a bond, lower alkyl, lower alkoxy, amino,        lower alkylamino, and sulfonamide;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, amino, carboxyl,        carboxamido, a carboxylic acid isostere, cyano, and tetrazole;    -   R₁₀ is chosen from null, hydrogen and lower alkyl; and    -   p is an integer chosen from 0, 1 or 2.

In yet further embodiments of Formula II,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula II, R₉ is a carboxylic acid isosterechosen from tetrazole, oxazole, isoxazole, isothiazole, —SO₃H, —SO₂NHR,—PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R, —NN(R)₂,—C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR, —C(O)NHNHSO₂R,—C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole, acyl sulfonamide,cyclobutenedione, cyclopentenedione, wherein R is hydrogen or a carbonchain or ring or a carbon-linked group, such as an alkyl, alkenyl,alkynyl, cycloalkyl, or aryl group, or a heterocycloalkyl or heteroarylgroup where the bond is to a carbon, any of which may be optionallysubstituted.

In further embodiments of Formula I, R₉ is a carboxylic acid isosterechosen from boronic acid, benzoxaborole, 3,3-dimethylbenzoxaborole,3-hydroxy-cyclopent-2-enone and cyclopentenedione.

In certain embodiments of Formula II, R₅ is heteroaryl.

In certain embodiments of Formula II, R₅ is a carboxylic acid isostere.

In certain embodiments of Formula II, R₅ is chosen from benzoxaborole,3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enone andcyclopentenedione.

In certain embodiments of Formula II, R₅ is benzoxaborole.

In yet further embodiments of Formula II,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula II, R₅ has the structure

wherein

-   -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and    -   q is an integer from 0 to 3.

In certain embodiments of Formula II, R₆ is chosen from:

-   -   substituted phenyl or naphthyl;    -   substituted monocyclic or bicyclic heteroaryl, having between        four and twelve ring atoms, of which up to six are heteroatoms        chosen from O, S, and N;    -   optionally substituted monocyclic or bicyclic heterocycloalkyl,        having between four and twelve ring atoms, of which up to six        are heteroatoms chosen from O, S, and N; and    -   optionally substituted monocyclic or bicyclic C₃-C₁₀ cycloalkyl.

In further embodiments of Formula II, R₆ is substituted with between oneand four substituents chosen from halogen, hydroxy, lower haloalkyl,lower alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and sulfonyl.

In certain further embodiments of Formula II, R₆ is substituted phenylor naphthyl.

In certain further embodiments of Formula II, R₆ is optionallysubstituted monocyclic heteroaryl, having between five and six ringatoms, of which up to four are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula II, R₆ is chosen from thiophene,pyrrole, pyrimidine, oxazole, isoxazole, pyrazole, imidazole, thiazole,isothiazole, pyridine, pyrazine and pyridazine, any of which may beoptionally substituted with between a substituent chosen from halogen,hydroxy, trifluoromethyl, methoxy.

In still further embodiments of Formula II, R₆ is thiophene.

In certain further embodiments of Formula II, R₆ is optionallysubstituted bicyclic heteroaryl, having between eight and nine ringatoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula II, R₆ is chosen from indole,benzoxazole, benzisoxazole, benzothiazole, quinoline, isoquinoline, andcoumarin.

In certain further embodiments of Formula II, R₆ is optionallysubstituted monocyclic heterocycloalkyl, having between five and sevenring atoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula II, R₆ is chosen from pyrrolidine,furan, morpholine, piperazine, and piperidine.

In further embodiments of Formula II, R₆ is optionally substitutedmonocyclic cycloalkyl having between five and seven ring atoms, andoptionally substituted monocyclic cycloalkoxy having between five andseven ring atoms.

In further embodiments of Formula II, R₆ is optionally substitutedcyclopentyl or optionally substituted cyclopentyloxy.

In further embodiments of Formula II, R₆ is optionally substitutedcyclopentyloxy.

In further embodiments of Formula II, R₆ is chosen from 3-chlorophenyland 5-chloro-2-thienyl.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula III:

or a salt, ester, amide, or prodrug thereof, wherein:

-   -   V₁ is chosen from CH₂, N, O, SO₂, and S;    -   V₂ is chosen from a bond, N, O and CH₂;    -   Y is chosen from O, NH, NR₂, CH₂, C(R₂)₂, S(O)_(n) and CO;    -   X is chosen from CH and N;    -   n is an integer chosen from 0, 1 or 2;    -   each R₂ is independently chosen from hydrogen, hydroxyl, and        lower alkyl;    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted;    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula III,

-   -   V₁ is chosen from CH₂, SO₂, and S; and    -   V₂ is chosen from a bond and CH₂;

In certain embodiments of Formula III, V₁ is SO₂ and V₂ is CH₂.

In certain embodiments of Formula III, V₁ is S and V₂ is CH₂.

In certain embodiments of Formula III, V₁ is CH₂ and V₂ is a bond.

In certain embodiments of Formula III, X is N.

In certain embodiments of Formula III, X is CH.

In certain embodiments of Formula III, Y is NH.

In certain embodiments of Formula III, Y is CH₂.

In other embodiments of Formula III, Y is O.

In certain embodiments of Formula III, Y is NR₂.

In certain embodiments of Formula III, R₅ is optionally substitutedaryl.

In certain embodiments of Formula III, R₅ is substituted phenyl, whichis either substituted in the ortho or meta position, or, if substitutedin the para position, contains at least one additional substituent.

In further embodiments of Formula III, R₅ is substituted with betweenone and four substituents of the form R₈—R₉—(R₁₀)_(p), wherein:

-   -   R₈ is chosen from a bond, lower alkyl, lower alkoxy, amino,        lower alkylamino, and sulfonamide;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, amino, carboxyl,        carboxamido, a carboxylic acid isostere, cyano, and tetrazole;    -   R₁₀ is chosen from null, hydrogen and lower alkyl; and    -   p is an integer chosen from 0, 1 or 2.

In yet further embodiments of Formula III,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula III, R₉ is a carboxylic acid isosterechosen from tetrazole, oxazole, isoxazole, isothiazole, —SO₃H, —SO₂NHR,—PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R, —NN(R)₂,—C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR, —C(O)NHNHSO₂R,—C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole, acyl sulfonamide,cyclobutenedione, cyclopentenedione, wherein R is hydrogen or a carbonchain or ring or a carbon-linked group, such as an alkyl, alkenyl,alkynyl, cycloalkyl, or aryl group, or a heterocycloalkyl or heteroarylgroup where the bond is to a carbon, any of which may be optionallysubstituted.

In further embodiments of Formula I, R₉ is a carboxylic acid isosterechosen from boronic acid, benzoxaborole, 3,3-dimethylbenzoxaborole,3-hydroxy-cyclopent-2-enone and cyclopentenedione.

In certain embodiments of Formula III, R₅ is heteroaryl.

In certain embodiments of Formula III, R₅ is a carboxylic acid isostere.

In certain embodiments of Formula III, R₅ is chosen from benzoxaborole,3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enone andcyclopentenedione.

In certain embodiments of Formula III, R₅ is benzoxaborole.

In yet further embodiments of Formula III,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula III, R₅ has the structure

wherein

-   -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and

In certain embodiments of Formula II, R₆ is chosen from:

-   -   substituted phenyl or naphthyl;    -   substituted monocyclic or bicyclic heteroaryl, having between        four and twelve ring atoms, of which up to six are heteroatoms        chosen from O, S, and N;    -   optionally substituted monocyclic or bicyclic heterocycloalkyl,        having between four and twelve ring atoms, of which up to six        are heteroatoms chosen from O, S, and N; and    -   optionally substituted monocyclic or bicyclic C₃-C₁₀ cycloalkyl.

In further embodiments of Formula III, R₆ is substituted with betweenone and four substituents chosen from halogen, hydroxy, lower haloalkyl,lower alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and sulfonyl.

In certain further embodiments of Formula III, R₆ is substituted phenylor naphthyl.

In certain further embodiments of Formula III, R₆ is optionallysubstituted monocyclic heteroaryl, having between five and six ringatoms, of which up to four are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula III, R₆ is chosen from thiophene,pyrrole, pyrimidine, oxazole, isoxazole, pyrazole, imidazole, thiazole,isothiazole, pyridine, pyrazine and pyridazine, any of which may beoptionally substituted with between a substituent chosen from halogen,hydroxy, trifluoromethyl, methoxy.

In still further embodiments of Formula III, R₆ is thiophene.

In certain further embodiments of Formula III, R₆ is optionallysubstituted bicyclic heteroaryl, having between eight and nine ringatoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula III, R₆ is chosen from indole,benzoxazole, benzisoxazole, benzothiazole, quinoline, isoquinoline, andcoumarin.

In certain further embodiments of Formula III, R₆ is optionallysubstituted monocyclic heterocycloalkyl, having between five and sevenring atoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula III, R₆ is chosen frompyrrolidine, furan, morpholine, piperazine, and piperidine.

In further embodiments of Formula III, R₆ is optionally substitutedmonocyclic cycloalkyl having between five and seven ring atoms, andoptionally substituted monocyclic cycloalkoxy having between five andseven ring atoms.

In further embodiments of Formula III, R₆ is optionally substitutedcyclopentyl or optionally substituted cyclopentyloxy.

In further embodiments of Formula III, R₆ is optionally substitutedcyclopentyloxy.

In further embodiments of Formula III, R₆ is chosen from 3-chlorophenyland 5-chloro-2-thienyl.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula IV:

or a salt, ester, amide, or prodrug thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, C(R₂)₂, S(O)_(n) and CO;    -   X is chosen from CH and N;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ is chosen from hydrogen, halogen, lower alkyl, hydroxyl,        trifluoromethyl, OR₂, and N(R₂)₂;    -   each R₂ is independently chosen from hydrogen, hydroxyl, and        lower alkyl;    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted;    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula IV, X is N.

In certain embodiments of Formula IV, X is CR₁.

In certain embodiments are provided compounds of structural Formula IVaor IVb:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, C(R₂)₂, S(O)_(n) and CO;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ (in Formula Iva only) is hydrogen;    -   each R₂ is independently chosen from hydrogen and lower alkyl;        and    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted; and    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula I IV, IVa, or IVb, R₁ is hydrogen.

In certain embodiments of Formula IV, IVa, or IVb, Y is NH.

In certain embodiments of Formula IV, IVa, or IVb, Y is CH₂.

In other embodiments of Formula IV, IVa, or IVb, Y is O.

In certain embodiments of Formula IV, IVa, or IVb, Y is NR₂.

In certain embodiments of Formula IV, IVa, or IVb, R₅ is optionallysubstituted aryl.

In certain embodiments of Formula IV, IVa, or IVb, R₅ is substitutedphenyl, which is either substituted in the ortho or meta position, or,if substituted in the para position, contains at least one additionalsubstituent.

In further embodiments of Formula IV, IVa, or IVb, R₅ is substitutedwith between one and four substituents of the form R₈—R₉—(R₁₀)_(p),wherein:

-   -   R₈ is chosen from a bond, lower alkyl, lower alkoxy, amino,        lower alkylamino, and sulfonamide;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, amino, carboxyl,        carboxamido, a carboxylic acid isostere, cyano, and tetrazole;    -   R₁₀ is chosen from null, hydrogen and lower alkyl; and    -   p is an integer chosen from 0, 1 or 2.

In yet further embodiments of Formula IV, IVa, or IVb,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula IV, IVa, or IVb, R₉ is a carboxylicacid isostere chosen from tetrazole, oxazole, isoxazole, isothiazole,—SO₃H, —SO₂NHR, —PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R,—NN(R)₂, —C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR,—C(O)NHNHSO₂R, —C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole,acyl sulfonamide, cyclobutenedione, cyclopentenedione, wherein R ishydrogen or a carbon chain or ring or a carbon-linked group, such as analkyl, alkenyl, alkynyl, cycloalkyl, or aryl group, or aheterocycloalkyl or heteroaryl group where the bond is to a carbon, anyof which may be optionally substituted.

In further embodiments of Formula I, R₉ is a carboxylic acid isosterechosen from boronic acid, benzoxaborole, 3,3-dimethylbenzoxaborole,3-hydroxy-cyclopent-2-enone and cyclopentenedione.

In certain embodiments of Formula IV, IVa, or IVb, R₅ is heteroaryl.

In certain embodiments of Formula IV, IVa, or IVb, R₅ is a carboxylicacid isostere.

In certain embodiments of Formula IV, IVa, or IVb, R₅ is chosen frombenzoxaborole, 3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enoneand cyclopentenedione.

In certain embodiments of Formula IV, IVa, or IVb, R₅ is benzoxaborole.

In yet further embodiments of Formula IV, IVa, or IVb,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula IV IVa or IVb, R₅ has the structure

wherein

-   -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and    -   q is an integer from 0 to 3.

In certain embodiments of Formula IV, IVa, or IVb, R₆ is chosen from:

-   -   substituted phenyl or naphthyl;    -   substituted monocyclic or bicyclic heteroaryl, having between        four and twelve ring atoms, of which up to six are heteroatoms        chosen from O, S, and N;    -   optionally substituted monocyclic or bicyclic heterocycloalkyl,        having between four and twelve ring atoms, of which up to six        are heteroatoms chosen from O, S, and N; and    -   optionally substituted monocyclic or bicyclic C₃-C₁₀ cycloalkyl.

In further embodiments of Formula IV, IVa, or IVb, R₆ is substitutedwith between one and four substituents chosen from halogen, hydroxy,lower haloalkyl, lower alkoxy, lower haloalkoxy, lower acyl, amino,cyano, and sulfonyl.

In certain further embodiments of Formula IV, IVa, or IVb, R₆ issubstituted phenyl or naphthyl.

In certain further embodiments of Formula IV, IVa, or IVb, R₆ isoptionally substituted monocyclic heteroaryl, having between five andsix ring atoms, of which up to four are heteroatoms chosen from O, S,and N.

In yet further embodiments of Formula IV, IVa, or IVb, R₆ is chosen fromthiophene, pyrrole, pyrimidine, oxazole, isoxazole, pyrazole, imidazole,thiazole, isothiazole, pyridine, pyrazine and pyridazine, any of whichmay be optionally substituted with between a substituent chosen fromhalogen, hydroxy, trifluoromethyl, methoxy.

In still further embodiments of Formula IV, IVa, or IVb, R₆ isthiophene.

In certain further embodiments of Formula IV, IVa, or IVb, R₆ isoptionally substituted bicyclic heteroaryl, having between eight andnine ring atoms, of which up to six are heteroatoms chosen from O, S,and N.

In yet further embodiments of Formula IV, IVa, or IVb, R₆ is chosen fromindole, benzoxazole, benzisoxazole, benzothiazole, quinoline,isoquinoline, and coumarin.

In certain further embodiments of Formula IV, IVa, or IVb, R₆ isoptionally substituted monocyclic heterocycloalkyl, having between fiveand seven ring atoms, of which up to six are heteroatoms chosen from O,S, and N.

In yet further embodiments of Formula IV, IVa, or IVb, R₆ is chosen frompyrrolidine, furan, morpholine, piperazine, and piperidine.

In further embodiments of Formula IV, IVa, or IVb, R₆ is optionallysubstituted monocyclic cycloalkyl having between five and seven ringatoms, and optionally substituted monocyclic cycloalkoxy having betweenfive and seven ring atoms.

In further embodiments of Formula IV, IVa, or IVb, R₆ is optionallysubstituted cyclopentyl or optionally substituted cyclopentyloxy.

In further embodiments of Formula IV, IVa, or IVb, R₆ is optionallysubstituted cyclopentyloxy.

In further embodiments of Formula IV, IVa, or IVb, R₆ is chosen from3-chlorophenyl and 5-chloro-2-thienyl.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula V:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, C(R₂)₂, S(O)_(n) and CO;    -   X is chosen from CH and N;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ (in Formula Va only) is hydrogen each R₂ is independently        chosen from hydrogen and lower alkyl; and    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted; and    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula V, X is N.

In certain embodiments of Formula V, X is CR₁.

In certain embodiments are provided compounds of structural Formula Vaor Vb:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, C(R₂)₂, S(O)_(n) and CO;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ (in Formula Va only) is hydrogen each R₂ is independently        chosen from hydrogen and lower alkyl; and    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted; and    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula V, Va, or Vb, Y is CH₂.

In certain embodiments of Formula V, Va, or Vb, Y is NH.

In other embodiments of Formula V, Va, or Vb, Y is O.

In certain embodiments of Formula V, Va, or Vb, Y is NR₂.

In certain embodiments of Formula V, Va, or Vb, R₅ is optionallysubstituted aryl.

In certain embodiments of Formula V, Va, or Vb, R₅ is substitutedphenyl, which is either substituted in the ortho or meta position, or,if substituted in the para position, contains at least one additionalsubstituent.

In further embodiments of Formula V, Va, or Vb, R₅ is substituted withbetween one and four substituents of the form R₈—R₉—(R₁₀)_(p), wherein:

-   -   R₈ is chosen from a bond, lower alkyl, lower alkoxy, amino,        lower alkylamino, and sulfonamide;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, amino, carboxyl,        carboxamido, a carboxylic acid isostere, cyano, and tetrazole;    -   R₁₀ is chosen from null, hydrogen and lower alkyl; and    -   p is an integer chosen from 0, 1 or 2.

In yet further embodiments of Formula V, Va, or Vb,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula V, Va, or Vb, R₉ is a carboxylic acidisostere chosen from tetrazole, oxazole, isoxazole, isothiazole, —SO₃H,—SO₂NHR, —PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R, —NN(R)₂,—C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR, —C(O)NHNHSO₂R,—C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole, acyl sulfonamide,cyclobutenedione, cyclopentenedione, wherein R is hydrogen or a carbonchain or ring or a carbon-linked group, such as an alkyl, alkenyl,alkynyl, cycloalkyl, or aryl group, or a heterocycloalkyl or heteroarylgroup where the bond is to a carbon, any of which may be optionallysubstituted.

In further embodiments of Formula V, Va, or Vb, R₉ is a carboxylic acidisostere chosen from boronic acid, benzoxaborole,3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enone andcyclopentenedione.

In certain embodiments of Formula V, Va, or Vb, R₅ is substitutedphenyl, which is either substituted in the ortho or meta position, or,if substituted in the para position, contains at least one additionalsubstituent.

In certain embodiments of Formula V, Va, or Vb, R₅ is heteroaryl.

In certain embodiments of Formula V, Va, or Vb, R₅ is a carboxylic acidisostere.

In certain embodiments of Formula V, Va, or Vb, R₅ is chosen frombenzoxaborole, 3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enoneand cyclopentenedione.

In certain embodiments of Formula V, Va, or Vb, R₅ is benzoxaborole.

In further embodiments of Formula V, Va, or Vb, R₅ has the structure

wherein

-   -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and    -   q is an integer from 0 to 3.

In yet further embodiments of Formula I,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In certain embodiments of Formula V, Va, or Vb, R₆ is chosen from:

-   -   substituted phenyl or naphthyl;    -   substituted monocyclic or bicyclic heteroaryl, having between        four and twelve ring atoms, of which up to six are heteroatoms        chosen from O, S, and N;    -   optionally substituted monocyclic or bicyclic heterocycloalkyl,        having between four and twelve ring atoms, of which up to six        are heteroatoms chosen from O, S, and N; and    -   optionally substituted monocyclic or bicyclic C₃-C₁₀ cycloalkyl.

In further embodiments of Formula V, Va, or Vb, R₆ is substituted withbetween one and four substituents chosen from halogen, hydroxy, lowerhaloalkyl, lower alkoxy, lower haloalkoxy, lower acyl, amino, cyano, andsulfonyl.

In certain further embodiments of Formula V, Va, or Vb, R₆ issubstituted phenyl or naphthyl.

In certain further embodiments of Formula V, Va, or Vb, R₆ is optionallysubstituted monocyclic heteroaryl, having between five and six ringatoms, of which up to four are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula V, Va, or Vb, R₆ is chosen fromthiophene, pyrrole, pyrimidine, oxazole, isoxazole, pyrazole, imidazole,thiazole, isothiazole, pyridine, pyrazine and pyridazine, any of whichmay be optionally substituted with between a substituent chosen fromhalogen, hydroxy, trifluoromethyl, methoxy.

In still further embodiments of Formula V, Va, or Vb, R₆ is thiophene.

In certain further embodiments of Formula V, Va, or Vb, R₆ is optionallysubstituted bicyclic heteroaryl, having between eight and nine ringatoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula V, Va, or Vb, R₆ is chosen fromindole, benzoxazole, benzisoxazole, benzothiazole, quinoline,isoquinoline, and coumarin.

In certain further embodiments of Formula V, Va, or Vb, R₆ is optionallysubstituted monocyclic heterocycloalkyl, having between five and sevenring atoms, of which up to six are heteroatoms chosen from O, S, and N.

In yet further embodiments of Formula V, Va, or Vb, R₆ is chosen frompyrrolidine, furan, morpholine, piperazine, and piperidine.

In further embodiments of Formula V, Va, or Vb, R₆ is optionallysubstituted monocyclic cycloalkyl having between five and seven ringatoms, and optionally substituted monocyclic cycloalkoxy having betweenfive and seven ring atoms.

In further embodiments of Formula V, Va, or Vb, R₆ is optionallysubstituted cyclopentyl or optionally substituted cyclopentyloxy.

In further embodiments of Formula V, Va, or Vb, R₆ is optionallysubstituted cyclopentyloxy.

In further embodiments of Formula V, Va, or Vb, R₆ is chosen from3-chlorophenyl and 5-chloro-2-thienyl.

Also provided are embodiments wherein any of embodiment above becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula VI,VII, VIII, or IX:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, C(R₂)₂, S(O)_(n) and CO;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ (in Formulas VI and IX) is hydrogen;    -   each R₂ is independently chosen from hydrogen and lower alkyl;    -   R₃ is chosen from lower alkyl and lower cycloalkyl; and    -   R₄ (in Formulas VI and VII) is chosen from hydrogen and lower        alkyl;    -   R₅ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, carboxylic acid, and a carboxylic acid isostere, any        of which may be optionally substituted; and    -   R₆ is chosen from aryl, heteroaryl, heterocycloalkyl,        cycloalkyl, lower alkoxy, lower cycloalkoxy, and lower        heterocycloalkoxy, any of which may be optionally substituted.

In certain embodiments of Formula VI, VII, VIII, or IX, Y is NR₂.

In certain embodiments of Formula VI, VII, VIII, or IX, Y is NH.

In certain embodiments of Formula VI, VII, VIII, or IX, Y is CH₂.

In other embodiments of Formula VI, VII, VIII, or IX, Y is O.

In certain embodiments of Formula VI, VII, VIII, or IX, R₅ is optionallysubstituted aryl.

certain embodiments of Formula VI, VII, VIII, or IX, R₅ is substitutedphenyl, which is either substituted in the ortho or meta position, or,if substituted in the para position, contains at least one additionalsubstituent.

In further embodiments of Formula VI, VII, VIII, or IX, R₅ issubstituted with between one and four substituents of the formR₈—R₉—(R₁₀)_(p), wherein:

-   -   R₈ is chosen from a bond, lower alkyl, lower alkoxy, amino,        lower alkylamino, and sulfonamide;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, amino, carboxyl,        carboxamido, a carboxylic acid isostere, cyano, and tetrazole;    -   R₁₀ is chosen from null, hydrogen and lower alkyl; and    -   p is an integer chosen from 0, 1 or 2.

In yet further embodiments of Formula VI, VII, VIII, or IX,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In further embodiments of Formula VI, VII, VIII, or IX, R₉ is acarboxylic acid isostere chosen from tetrazole, oxazole, isoxazole,isothiazole, —SO₃H, —SO₂NHR, —PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂,—NHC(O)R, —NN(R)₂, —C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR,—C(O)NHNHSO₂R, —C(O)NHSO₂R, —C(O)ONRCN, boronic acid, benzoxaborole,acyl sulfonamide, cyclobutenedione, cyclopentenedione, wherein R ishydrogen or a carbon chain or ring or a carbon-linked group, such as analkyl, alkenyl, alkynyl, cycloalkyl, or aryl group, or aheterocycloalkyl or heteroaryl group where the bond is to a carbon, anyof which may be optionally substituted.

In further embodiments of Formula VI, VII, VIII, or IX, R₉ is acarboxylic acid isostere chosen from boronic acid, benzoxaborole,3,3-dimethylbenzoxaborole, 3-hydroxy-cyclopent-2-enone andcyclopentenedione.

In certain embodiments of Formula VI, VII, VIII, or IX, R₅ isheteroaryl.

In certain embodiments of Formula VI, VII, VIII, or IX, R₅ is acarboxylic acid isostere.

In certain embodiments of Formula VI, VII, VIII, or IX, R₅ is chosenfrom benzoxaborole, 3,3-dimethylbenzoxaborole,3-hydroxy-cyclopent-2-enone and cyclopentenedione.

In certain embodiments of Formula VI, VII, VIII, or IX, R₅ isbenzoxaborole.

In further embodiments of Formula VI, VII, VIII, or IX, R₅ has thestructure

wherein

-   -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and    -   q is an integer from 0 to 3.

In yet further embodiments of Formula VI, VII, VIII, or IX,

-   -   R₈ is chosen from a bond, methyl, ethyl, methoxy, and ethoxy;        and    -   R₉ is chosen from methyl, ethyl, methoxy, ethoxy, fluorine,        chlorine, bromine, perfluoromethyl, perfluoromethoxy, carboxyl,        carboxamide, cyano, and tetrazole.

In certain embodiments of Formula VI, VII, VIII, or IX, R₆ is chosenfrom:

-   -   substituted phenyl or naphthyl;    -   substituted monocyclic or bicyclic heteroaryl, having between        four and twelve ring atoms, of which up to six are heteroatoms        chosen from O, S, and N;    -   optionally substituted monocyclic or bicyclic heterocycloalkyl,        having between four and twelve ring atoms, of which up to six        are heteroatoms chosen from O, S, and N; and    -   optionally substituted monocyclic or bicyclic C₃-C₁₀ cycloalkyl.

In further embodiments of Formula VI, VII, VIII, or IX, R₆ issubstituted with between one and four substituents chosen from halogen,hydroxy, lower haloalkyl, lower alkoxy, lower haloalkoxy, lower acyl,amino, cyano, and sulfonyl.

In certain further embodiments of Formula VI, VII, VIII, or IX, R₆ issubstituted phenyl or naphthyl.

In certain further embodiments of Formula VI, VII, VIII, or IX, R₆ isoptionally substituted monocyclic heteroaryl, having between five andsix ring atoms, of which up to four are heteroatoms chosen from O, S,and N.

In yet further embodiments of Formula VI, VII, VIII, or IX, R₆ is chosenfrom thiophene, pyrrole, pyrimidine, oxazole, isoxazole, pyrazole,imidazole, thiazole, isothiazole, pyridine, pyrazine and pyridazine, anyof which may be optionally substituted with between a substituent chosenfrom halogen, hydroxy, trifluoromethyl, methoxy.

In still further embodiments of Formula VI, VII, VIII, or IX, R₆ isthiophene.

In certain further embodiments of Formula VI, VII, VIII, or IX, R₆ isoptionally substituted bicyclic heteroaryl, having between eight andnine ring atoms, of which up to six are heteroatoms chosen from O, S,and N.

In yet further embodiments of Formula VI, VII, VIII, or IX, R₆ is chosenfrom indole, benzoxazole, benzisoxazole, benzothiazole, quinoline,isoquinoline, and coumarin.

In certain further embodiments of Formula VI, VII, VIII, or IX, R₆ isoptionally substituted monocyclic heterocycloalkyl, having between fiveand seven ring atoms, of which up to six are heteroatoms chosen from O,S, and N.

In yet further embodiments of Formula VI, VII, VIII, or IX, R₆ is chosenfrom pyrrolidine, furan, morpholine, piperazine, and piperidine.

In further embodiments of Formula VI, VII, VIII, or IX, R₆ is optionallysubstituted monocyclic cycloalkyl having between five and seven ringatoms, and optionally substituted monocyclic cycloalkoxy having betweenfive and seven ring atoms.

In further embodiments of Formula VI, VII, VIII, or IX, R₆ is optionallysubstituted cyclopentyl or optionally substituted cyclopentyloxy.

In further embodiments of Formula VI, VII, VIII, or IX, R₆ is optionallysubstituted cyclopentyloxy.

In further embodiments of Formula VI, VII, VIII, or IX, R₆ is chosenfrom 3-chlorophenyl and 5-chloro-2-thienyl.

In certain embodiments of Formula VI, VII, VIII, or IX, R₃ is chosenfrom lower alkyl, lower cycloalkyl, and trifluoromethyl.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula X:

or a salt, ester, amide, or prodrug thereof, wherein:

-   -   X is chosen from CR₁ and N;    -   Y is chosen from O, NH, NR₂, CH₂, C(R₂)₂, S(O)_(n) and CO;    -   Z is chosen from C and N;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ is chosen from hydrogen, halogen, lower alkyl, hydroxyl, OR₂,        and N(R₂)₂; Each R₂ is independently chosen from hydrogen and        lower alkyl;    -   R₃ is chosen from lower alkyl and lower cycloalkyl;    -   R₄ is chosen from:        -   null if Z is N; and        -   hydrogen, heteroalkyl, and lower alkyl if Z is C;    -   or R₃ and R₄, together with the atoms to which they are        attached, join to form a 4 to 7 membered ring, which may be        optionally substituted;    -   R₁₁ and R₁₂ are independently chosen from hydrogen and lower        alkyl;    -   each R₁₃ is chosen from halogen, hydroxy, lower haloalkyl, lower        alkoxy, lower haloalkoxy, lower acyl, amino, cyano, and        sulfonyl; and    -   q is an integer from 0 to 3.

In certain embodiments of Formula X, Z is C.

In other embodiments of Formula X, Z is N.

In certain embodiments of Formula X, X is N.

In certain embodiments of Formula X, X is CR₁.

In certain embodiments of Formula X, R₁ is hydrogen.

In certain embodiments of Formula X, R₃ and R₄ join to form a 4- to7-membered cycloalkyl or heterocycloalkyl.

In certain embodiments of Formula X, R₃ and R₄ join to form a 5-memberedcycloalkyl or 5- or 6-membered heterocycloalkyl.

In certain embodiments of Formula X,

-   -   R₃ and is chosen from lower alkyl, lower cycloalkyl, and        trifluoromethyl;    -   R₄ is chosen from hydrogen and lower alkyl.

In certain embodiments of Formula X, R₃ and R₄ are each lower alkyl.

In certain embodiments of Formula X:

-   -   R₃ and R₄ are each lower alkyl; and    -   Z is C.

In certain embodiments of Formula X, R₃ and R₄ are each chosen frommethyl and ethyl.

In certain embodiments of Formula X, R₃ is methyl and R₄ is ethyl.

In certain embodiments of Formula X, R₃ is ethyl and R₄ is hydrogen.

In certain embodiments of Formula X, R₃ is trifluoromethyl and R₄ ishydrogen.

In certain embodiments of Formula X, R₃ is cyclopropyl and R₄ ishydrogen.

In certain embodiments of Formula X, the compound has a structure chosenfrom:

In certain embodiments of Formula X, the compound has a structure chosenfrom:

In certain embodiments of Formula X, R₄ is null.

In certain embodiments of Formula X, Y is CH₂.

In certain embodiments of Formula X, Y is NH.

In other embodiments of Formula X, Y is O.

In certain embodiments of Formula X, Y is NR₂.

In certain embodiments of Formula X wherein Z is C, X is N, and R₅ issubstituted phenyl, the phenyl is either substituted in the ortho ormeta position, or, if substituted in the para position, contains atleast one additional substituent.

In certain further embodiments of Formula X, R₁ is chosen from hydrogen,halogen, hydroxyl, and NH₂.

In certain further embodiments of Formula X:

-   -   R₁ is chosen from lower alkyl, OR₂, and N(R₂)₂; and    -   at least one of R₂ is lower alkyl.

In further embodiments of Formula X, R₂ is chosen from methyl, ethyl,propyl, isopropyl, butyl, and t-butyl.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula XI:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, NR₂, CH₂, C(R₂)₂, and S(O)_(n);    -   X is chosen from CH and N;    -   n is an integer chosen from 0, 1 or 2;    -   each R₂ is independently chosen from hydrogen and lower alkyl;    -   R₃ is chosen from methyl, ethyl, and cyclopropyl;    -   R₄ is chosen from hydrogen and ethyl;    -   or R₃ and R₄, together with the atoms to which they are        attached, join to form a 5 to 6 membered cycloalkyl or        heterocycloalkyl of the form:

-   -   V₁ is chosen from CH₂, N, O, SO₂, and S;    -   V₂ is chosen from a bond, N, O and CH₂;    -   R₅ is either benzoxaborole, or is chosen from phenyl and        pyridinyl, either of which is para-substituted with a        substituent of the form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is        optionally substituted with a substituent R₁₃;    -   R₅ is chosen from a bond and lower alkyl;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, cyano, —C(O)N—,        S(O)₂—, B(OH)₂, 5-6 membered monocyclic heterocycloalkyl, and        5-6 membered monocyclic heteroaryl;    -   (R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,        hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl,        lower hydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O        lower alkyl;    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano;    -   R₆ is chosen from 3-chlorophenyl, 5-chloro-2-thienyl,        cyclopentyl optionally substituted with one or two R₁₄, and        cyclopentoxy optionally substituted with one or two R₁₄; and    -   R₁₃ and R₁₄ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano

In certain embodiments of Formula XI, R₅ is either benzoxaborole, or isphenyl which is para-substituted with a substituent of the formR—R₉—(R₁₀)_(a)(R₁₀)_(b), and is optionally substituted with asubstituent R₁₃.

In certain embodiments of Formula XI, Y is chosen from O, NH, and CH₂.

In certain embodiments of Formula XI, Y is NH.

In certain embodiments of Formula XI, Y is CH₂.

In certain embodiments of Formula XI, R₉ is chosen from 5-6 memberedmonocyclic heterocycloalkyl, and 5-6 membered monocyclic heteroaryl.

In certain embodiments of Formula XI,

-   -   R₉ is —C(O)N—;    -   R_(10a) is lower hydroxyalkyl; and    -   R_(10b) is null.

In certain embodiments of Formula XI,

-   -   R₉ is —C(O)N—;    -   R_(10a) is cyano; and    -   R_(10b) is null.

In certain embodiments of Formula XI, R₉ is lower hydroxyalkyl.

In certain embodiments of Formula XI, R₉ is chosen from methanol,ethanol, isopropanol, N-propanol, and t-butanol.

In certain embodiments of Formula XI, R₉ is chosen from ethanol andN-propanol.

In certain embodiments of Formula XI, —R₉—(R₁₀)_(a)(R₁₀)_(b) is chosenfrom:

In certain embodiments of Formula XI, —R₉—(R₁₀)_(a)(R₁₀)_(b) is chosenfrom:

In certain embodiments of Formula XI, R₈ is a bond.

In certain embodiments of Formula XI, R₈ is lower alkyl.

In certain embodiments of Formula XI, R₈ is methyl.

In certain embodiments of Formula XI, X is N.

In certain embodiments of Formula XI, X is CH.

In certain embodiments of Formula XI, R₅ is benzoxaborole.

In certain embodiments of Formula XI, R₅ is phenyl which ispara-substituted with a substituent of the formR₈—R₉—(R₁₀)_(a)(R₁₀)_(b).

In certain embodiments of Formula XI, R₆ is chosen from 3-chlorophenyland 5-chloro-2-thienyl.

In certain embodiments of Formula XI, R₆ is 3-chlorophenyl.

In certain embodiments of Formula XI, R₆ is 5-chloro-2-thienyl.

In certain embodiments of Formula XI, R₆ is chosen from cyclopentyloptionally substituted with one or two R₁₄, and cyclopentoxy optionallysubstituted with one or two R₁₄.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

In certain embodiments are provided compounds of structural Formula XII:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, and CH₂;    -   X is chosen from CH and N;    -   V₁ is chosen from CH₂, N, O, SO₂, and S;    -   V₂ is chosen from a bond, N, O and CH₂;    -   R₅ is either benzoxaborole, or is chosen from phenyl and        pyridinyl, either of which is para-substituted with a        substituent of the form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is        optionally substituted with a substituent R₁₃;    -   R₈ is chosen from a bond and lower alkyl;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, cyano, —C(O)N—,        S(O)₂—, B(OH)₂, 5-6 membered monocyclic heterocycloalkyl, and        5-6 membered monocyclic heteroaryl;    -   (R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,        hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl,        lower hydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O        lower alkyl;    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano;    -   R₆ is chosen from 3-chlorophenyl, 5-chloro-2-thienyl,        cyclopentyl optionally substituted with one or two R₁₄, and        cyclopentoxy optionally substituted with one or two R₁₄; and    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano.

In certain embodiments of Formula XII are provided compounds having astructural formula chosen from structural Formulas XIIa, XIIb, XIIc,XIId, XIIe, and XIIf:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, and CH₂;    -   X is chosen from CH and N;    -   R₅ is either benzoxaborole, or is chosen from phenyl and        pyridinyl, either of which is para-substituted with a        substituent of the form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is        optionally substituted with a substituent R₁₃;    -   R₈ is chosen from a bond and lower alkyl;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, cyano, —C(O)N—,        S(O)₂—, B(OH)₂, 5-6 membered monocyclic heterocycloalkyl, and        5-6 membered monocyclic heteroaryl;    -   (R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,        hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl,        lower hydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O        lower alkyl;    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano;    -   R₆ is chosen from 3-chlorophenyl, 5-chloro-2-thienyl,        cyclopentyl optionally substituted with one or two R₁₄, and        cyclopentoxy optionally substituted with one or two R₁₄; and    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano.

In certain embodiments are provided compounds of any of structuralFormulas XIII, XIV, XV, and XVI:

or a salt thereof, wherein:

-   -   Y is chosen from O, NH, and CH₂;    -   X is chosen from CH and N;    -   R₅ is either benzoxaborole, or is chosen from phenyl and        pyridinyl, either of which is para-substituted with a        substituent of the form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is        optionally substituted with a substituent R₁₃;    -   R₈ is chosen from a bond and lower alkyl;    -   R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lower        hydroxyalkyl, lower alkoxy, lower haloalkoxy, cyano, —C(O)N—,        S(O)₂—, B(OH)₂, 5-6 membered monocyclic heterocycloalkyl, and        5-6 membered monocyclic heteroaryl;    -   (R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,        hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl,        lower hydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O        lower alkyl;    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano;    -   R₆ is chosen from 3-chlorophenyl, 5-chloro-2-thienyl,        cyclopentyl optionally substituted with one or two R₁₄, and        cyclopentoxy optionally substituted with one or two R₁₄; and    -   R₁₃ is chosen from halogen, hydroxy, lower alkyl,        trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, R₅ is either benzoxaborole, or is phenyl which is para-substitutedwith a substituent of the form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and isoptionally substituted with a substituent R₁₃.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, Y is chosen from O, NH, and CH₂.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, Y is NH.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, Y is CH₂.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI,

-   -   R₉ is —C(O)N—;    -   R_(10a) is lower hydroxyalkyl; and    -   R_(10b) is null.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI,

-   -   R₉ is —C(O)N—;    -   R_(10a) is cyano; and    -   R_(10b) is null.

In certain embodiments of Formula XII, XIIa-XIIf, XIII, XIV, XV, andXVI, R₉ is lower hydroxyalkyl.

In certain embodiments of Formula XII, XIIa-XIIf, XIII, XIV, XV, andXVI, R₉ is chosen from methanol, ethanol, isopropanol, N-propanol, andt-butanol.

In certain embodiments of Formula XII, XIIa-XIIf, XIII, XIV, XV, andXVI, R₉ is chosen from ethanol and N-propanol.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, R₉ is chosen from 5-6 membered monocyclic heterocycloalkyl, and 5-6membered monocyclic heteroaryl.

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, —R₉—(R₁₀)_(a)(R₁₀)_(b) is chosen from:

In certain embodiments of Formulas XII, XIIa-XIIf, XIII, XIV, XV, andXVI, —R₉—(R₁₀)_(a)(R₁₀)_(b) is chosen from:

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₈ is a bond.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₈ is lower alkyl.

In certain embodiments of Formula XII, XIIa-XIIf, XIII, XIV, XV, andXVI, R₈ is methyl.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, X is N.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, X is CH.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₅ is benzoxaborole.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₅ is phenyl which is para-substituted with a substituent ofthe form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b).

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₆ is chosen from 3-chlorophenyl and 5-chloro-2-thienyl.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₆ is 3-chlorophenyl.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₆ is 5-chloro-2-thienyl.

In certain embodiments of any of Formulas XII, XIIa-XIIf, XIII, XIV, XV,and XVI, R₆ is chosen from cyclopentyl optionally substituted with oneor two R₁₄, and cyclopentoxy optionally substituted with one or two R₁₄.

Also provided are embodiments wherein any of embodiment above may becombined with any one or more of these embodiments, provided thecombination is not mutually exclusive.

Also provided are compounds of structural Formula Ia:

or a salt thereof, wherein:

-   -   X is chosen from CR₁ and N;    -   Y is chosen from O, NH, NR₂, C(R₂)₂, S(O)_(n) and CO;    -   Z is chosen from C and N;    -   n is an integer chosen from 0, 1 or 2;    -   R₁ is chosen from hydrogen, halogen, lower alkyl, hydroxyl, OR₂,        and N(R₂)₂;    -   each R₂ is independently chosen from hydrogen and lower alkyl;    -   R₃ is chosen from lower alkyl and lower cycloalkyl;    -   R₄ is chosen from:        -   null if Z is N; and        -   hydrogen or lower alkyl if Z is C;    -   or R₃ and R₄, together with the atoms to which they are        attached, join to form a 4 to 7 membered ring, which may be        optionally substituted; and    -   R₅ and R₆ are each independently chosen from aryl, heteroaryl,        heterocycloalkyl, cycloalkyl, and a carboxylic acid isostere,        any of which may be optionally substituted.

Each embodiment as disclosed in each of the priority applications ofthis application is explicitly incorporated by reference as if writtenherein in its entirety.

Also provided is a compound chosen from the Examples disclosed herein.

The present invention also relates to a method of inhibiting at leastone PDE4 function comprising the step of contacting the PDE4 with acompound of Formula I, as described herein. The cell phenotype, cellproliferation, activity of PDE4, change in biochemical output producedby active PDE4, expression of PDE4, or binding of PDE4 with a naturalbinding partner may be monitored. Such methods may be modes of treatmentof disease, biological assays, cellular assays, biochemical assays, orthe like.

Also provided herein is a method of treatment of a PDE4-mediated diseasecomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient in needthereof.

In certain embodiments, the disease is chosen from depression,depression secondary to illness, Alzheimer's disease, and traumaticbrain injury.

Also provided herein is a compound as disclosed herein for use as amedicament.

Also provided herein is a compound as disclosed herein for use as amedicament for the treatment of a PDE4-mediated disease.

Also provided is the use of a compound as disclosed herein as amedicament.

Also provided is the use of a compound as disclosed herein as amedicament for the treatment of a PDE4-mediated disease.

Also provided is a compound as disclosed herein for use in themanufacture of a medicament for the treatment of a PDE4-mediateddisease.

Also provided is the use of a compound as disclosed herein for thetreatment of a PDE4-mediated disease.

Also provided herein is a method of inhibition of PDE4 comprisingcontacting PDE4 with a compound as disclosed herein, or a salt thereof.

Also provided herein is a method for achieving an effect in a patientcomprising the administration of a therapeutically effective amount of acompound as disclosed herein, or a salt thereof, to a patient, whereinthe effect is chosen from cognition enhancement.

Compounds of the present invention may be selective amongst the PDE4isoforms PDE4A, PDE4B, PDE4C, and PDE4D in various ways. For example,compounds described herein may be selective for PDE4B and/or PDE4D overthe other two isoforms, be a pan-inhibitor of all the isoforms, or beselective for only one isoform. In certain embodiments, compounds of thepresent invention may be selective for PDE4B over other isoforms.

In certain embodiments, the PDE4 is PDE4D.

In certain embodiments, the PDE4 is PDE4B.

In certain embodiments, the PDE4B-mediated disease is chosen fromdepression and depression secondary to illness.

Also provided is a method of modulation of a PDE4-mediated function in asubject comprising the administration of a therapeutically effectiveamount of a compound as disclosed herein.

In certain embodiments, the PDE4 is PDE4.

In certain embodiments, the modulation is enhancement.

In certain embodiments, the function is cognition.

Also provided is a pharmaceutical composition comprising a compound asdisclosed herein, together with a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition is formulated fororal administration.

As used herein, the terms below have the meanings indicated.

When ranges of values are disclosed, and the notation “from n₁ . . . ton₂” or “between n₁ . . . and n₂” is used, where n₁ and n₂ are thenumbers, then unless otherwise specified, this notation is intended toinclude the numbers themselves and the range between them. This rangemay be integral or continuous between and including the end values. Byway of example, the range “from 2 to 6 carbons” is intended to includetwo, three, four, five, and six carbons, since carbons come in integerunits. Compare, by way of example, the range “from 1 to 3 μM(micromolar),” which is intended to include 1 μM, 3 μM, and everythingin between to any number of significant figures (e.g., 1.255 μM, 2.1 μM,2.9999 μM, etc.). When n is set at 0 in the context of “0 carbon atoms”,it is intended to indicate a bond or null.

The term “about,” as used herein, is intended to qualify the numericalvalues which it modifies, denoting such a value as variable within amargin of error. When no particular margin of error, such as a standarddeviation to a mean value given in a chart or table of data, is recited,the term “about” should be understood to mean that range which wouldencompass the recited value and the range which would be included byrounding up or down to that figure as well, taking into accountsignificant figures.

The term “acyl,” as used herein, alone or in combination, refers to acarbonyl attached to an alkenyl, alkyl, aryl, cycloalkyl, heteroaryl,heterocycle, or any other moiety where the atom attached to the carbonylis carbon. An “acetyl” group refers to a —C(O)CH₃ group. An“alkylcarbonyl” or “alkanoyl” group refers to an alkyl group attached tothe parent molecular moiety through a carbonyl group. Examples of suchgroups include methylcarbonyl and ethylcarbonyl. Examples of acyl groupsinclude formyl, alkanoyl and aroyl.

The term “alkenyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon group having one or moredouble bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkenyl will comprise from 2 to 6 carbon atoms. Theterm “alkenylene” refers to a carbon-carbon double bond system attachedat two or more positions such as ethenylene [(—CH═CH—),(—C::C—)].Examples of suitable alkenyl groups include ethenyl, propenyl,2-methylpropenyl, 1,4-butadienyl and the like. Unless otherwisespecified, the term “alkenyl” may include “alkenylene” groups.

The term “alkoxy,” as used herein, alone or in combination, refers to analkyl ether group, wherein the term alkyl is as defined below. Examplesof suitable alkyl ether groups include methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, and the like.

The term “alkyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain alkyl group containing from 1 to 20carbon atoms. In certain embodiments, said alkyl will comprise from 1 to10 carbon atoms. In further embodiments, said alkyl will comprise from 1to 6 carbon atoms. Alkyl groups may be optionally substituted as definedherein. Examples of alkyl groups include methyl, ethyl, n-propyl,isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl,hexyl, octyl, noyl and the like. The term “alkylene,” as used herein,alone or in combination, refers to a saturated aliphatic group derivedfrom a straight or branched chain saturated hydrocarbon attached at twoor more positions, such as methylene (—CH₂—). Unless otherwisespecified, the term “alkyl” may include “alkylene” groups.

The term “alkylamino,” as used herein, alone or in combination, refersto an alkyl group attached to the parent molecular moiety through anamino group. Suitable alkylamino groups may be mono- or dialkylated,forming groups such as, for example, N-methylamino, N-ethylamino,N,N-dimethylamino, N,N-ethylmethylamino and the like.

The term “alkylidene,” as used herein, alone or in combination, refersto an alkenyl group in which one carbon atom of the carbon-carbon doublebond belongs to the moiety to which the alkenyl group is attached.

The term “alkylthio,” as used herein, alone or in combination, refers toan alkyl thioether (R—S—) group wherein the term alkyl is as definedabove and wherein the sulfur may be singly or doubly oxidized. Examplesof suitable alkyl thioether groups include methylthio, ethylthio,n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio,tert-butylthio, methanesulfonyl, ethanesulfinyl, and the like.

The term “alkynyl,” as used herein, alone or in combination, refers to astraight-chain or branched-chain hydrocarbon group having one or moretriple bonds and containing from 2 to 20 carbon atoms. In certainembodiments, said alkynyl comprises from 2 to 6 carbon atoms. In furtherembodiments, said alkynyl comprises from 2 to 4 carbon atoms. The term“alkynylene” refers to a carbon-carbon triple bond attached at twopositions such as ethynylene (—C:::C—, —C≡C—). Examples of alkynylgroups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl,butyn-2-yl, pentyn-1-yl, 3-methylbutyn-1-yl, hexyn-2-yl, and the like.Unless otherwise specified, the term “alkynyl” may include “alkynylene”groups.

The terms “amido” and “carbamoyl,” as used herein, alone or incombination, refer to an amino group as described below attached to theparent molecular moiety through a carbonyl group, or vice versa. Theterm “C-amido” as used herein, alone or in combination, refers to a—C(═O)—NR₂ group with R as defined herein. The term “N-amido” as usedherein, alone or in combination, refers to a RC(═O)NH— group, with R asdefined herein. The term “acylamino” as used herein, alone or incombination, embraces an acyl group attached to the parent moietythrough an amino group. An example of an “acylamino” group isacetylamino (CH₃C(O)NH—).

The term “amino,” as used herein, alone or in combination, refers to—NRR′, wherein R and R′ are independently chosen from hydrogen, alkyl,hydroxyalkyl, acyl, heteroalkyl, aryl, cycloalkyl, heteroaryl, andheterocycloalkyl, any of which may themselves be optionally substituted.Additionally, R and R′ may combine to form heterocycloalkyl, either ofwhich may be optionally substituted.

The term “amino acid”, as used herein, alone or in combination, refersto a —NHCHRC(O)O— group, which may be attached to the parent molecularmoiety to give either an N-terminus or C-terminus amino acid, wherein Ris independently chosen from hydrogen, alkyl, aryl, heteroaryl,heterocycloalkyl, aminoalkyl, amido, amidoalkyl, carboxyl,carboxylalkyl, guanidinealkyl, hydroxyl, thiol, and thioalkyl, any ofwhich themselves may be optionally substituted. The term C-terminus, asused herein, alone or in combination, refers to the parent molecularmoiety being bound to the amino acid at the amino group, to give anamide as described herein, with the carboxyl group unbound, resulting ina terminal carboxyl group, or the corresponding carboxylate anion. Theterm N-terminus, as used herein, alone or in combination, refers to theparent molecular moiety being bound to the amino acid at the carboxylgroup, to give an ester as described herein, with the amino groupunbound resulting in a terminal secondary amine, or the correspondingammonium cation. In other words, C-terminus refers to —NHCHRC(O)OH or to—NHCHRC(O)O⁻ and N-terminus refers to H₂NCHRC(O)O— or to H₃N⁺CHRC(O)O—.

The term “aryl”, as used herein, alone or in combination, means acarbocyclic aromatic system containing one, two or three rings whereinsuch polycyclic ring systems are fused together. The term “aryl”embraces aromatic groups such as phenyl, naphthyl, anthracenyl, andphenanthryl.

The term “arylalkenyl” or “aralkenyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkenyl group.

The term “arylalkoxy” or “aralkoxy,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkoxy group.

The term “arylalkyl” or “aralkyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkyl group.

The term “arylalkynyl” or “aralkynyl,” as used herein, alone or incombination, refers to an aryl group attached to the parent molecularmoiety through an alkynyl group.

The term “arylalkanoyl” or “aralkanoyl” or “aroyl,” as used herein,alone or in combination, refers to an acyl group derived from anaryl-substituted alkanecarboxylic acid such as benzoyl, naphthoyl,phenylacetyl, 3-phenylpropionyl (hydrocinnamoyl), 4-phenylbutyryl,(2-naphthyl)acetyl, 4-chlorohydrocinnamoyl, and the like.

The term aryloxy as used herein, alone or in combination, refers to anaryl group attached to the parent molecular moiety through an oxy.

The terms “benzo” and “benz,” as used herein, alone or in combination,refer to the divalent group C₆H₄=derived from benzene. Examples includebenzothiophene and benzimidazole.

The term “benzoxaborole” may be used to refer to any of the followingstructures, and may encompass both substituted and unsubstitutedexamples:

The term “carbamate,” as used herein, alone or in combination, refers toan ester of carbamic acid (—NHCOO—) which may be attached to the parentmolecular moiety from either the nitrogen or acid end, and which may beoptionally substituted as defined herein.

The term “O-carbamyl” as used herein, alone or in combination, refers toa —OC(O)NRR′ group, with R and R′ as defined herein.

The term “N-carbamyl” as used herein, alone or in combination, refers toa ROC(O)NR′— group, with R and R′ as defined herein.

The term “carbonyl,” as used herein, when alone includes formyl [—C(O)H]and in combination is a —C(O)— group.

The term “carboxyl” or “carboxy,” as used herein, refers to —C(O)OH(“carboxylic acid”) or the corresponding “carboxylate” anion, such as isin a carboxylic acid salt. An “O-carboxy” group refers to a RC(O)O—group, where R is as defined herein. A “C-carboxy” group refers to a—C(O)OR groups where R is as defined herein.

“Isosteres” are different compounds that have different molecularformulae but exhibit the same or similar properties. For example,tetrazole is an isostere of carboxylic acid because it mimics theproperties of carboxylic acid even though they both have differentmolecular formulae. Tetrazole is one of many possible isostericreplacements for carboxylic acid. Other carboxylic acid isosterescontemplated by the present invention include —RC(O)OH, —SO₃H, —SO₂NHR,—PO₂(R)₂, —CN, —PO₃(R)₂, —OR, —SR, —N(R)₂, —NHC(O)R, —NN(R)₂,—C(O)N(R)₂, —RC(O)N(CN)H, —N(CN)C(O)(R), —C(O)NHOR, —C(O)NHNHSO₂R,—C(O)NHSO₂R, —C(O)ONRCN, boronic acid and boronic acid analogues such asbenzoxaborole, and acyl sulfonamide, wherein each R may be the same ordifferent and is is chosen from hydrogen, a carbon chain or ring or acarbon-linked group, such as an alkyl, alkenyl, alkynyl, cycloalkyl, oraryl group, and a heterocycloalkyl or heteroaryl group where the bond isto a carbon, any of which may be optionally substituted.

In addition, carboxylic acid isosteres can include 4-7 memberedcarbocycles or heterocycles (aromatic and non-aromatic) containing anycombination of C, O, S, or N in any chemically stable oxidation state,where any of the atoms of said ring structure are optionally substitutedin one or more positions. Examples of carbocyclic and heterocyclicisosteres contemplated include squaric acid and derivatives such ascyclobutenediones (e.g. 3-hydroxy-cyclobutene-1,2-dione and3,4-diamino-3-cyclobutene-1,2-dione), cyclopentadiones, and heterocyclicgroups such as:

In addition, carboxylic acid isosteres can include carboxylic acidswhich are themselves substituted with isosteric functional groups.Examples of such groups include:

The present invention contemplates that when chemical substituents areadded to a carboxylic isostere then the inventive compound retains theproperties of a carboxylic isostere. The present invention contemplatesthat when a carboxylic isostere is optionally substituted with one ormore moieties selected from R3, then the substitution cannot eliminatethe carboxylic acid isosteric properties of the inventive compound. Thepresent invention contemplates that the placement of one or more R3substituents upon a carbocyclic or heterocyclic carboxylic acid isostereshall not be permitted at one or more atom(s) which maintain(s) oris/are integral to the carboxylic acid isosteric properties of theinventive compound, if such substituent(s) would destroy the carboxylicacid isosteric properties of the inventive compound.

Other carboxylic acid isosteres not specifically exemplified ordescribed in this specification are also contemplated by the presentinvention.

The term “cyano,” as used herein, alone or in combination, refers to—CN.

The term “cycloalkyl,” or, alternatively, “carbocycle,” as used herein,alone or in combination, refers to a saturated or partially saturatedmonocyclic, bicyclic or tricyclic alkyl group wherein each cyclic moietycontains from 3 to 12 carbon atom ring members and which may optionallybe a benzo fused ring system which is optionally substituted as definedherein, provided that at least one of the rings is non-aromatic. Incertain embodiments, said cycloalkyl will comprise from 5 to 7 carbonatoms. Examples of such cycloalkyl groups include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronapthyl,indanyl, octahydronaphthyl, 2,3-dihydro-1H-indenyl, adamantyl and thelike. “Bicyclic” and “tricyclic” as used herein are intended to includeboth fused ring systems, such as decahydronaphthalene,octahydronaphthalene as well as the multicyclic (multicentered)saturated or partially unsaturated type. The latter type of isomer isexemplified in general by, bicyclo[1,1,1]pentane, camphor, adamantane,andbicyclo[3,2,1]octane.

The term “ester,” as used herein, alone or in combination, refers to acarboxy group bridging two moieties linked at carbon atoms.

The term “ether,” as used herein, alone or in combination, refers to anoxy group bridging two moieties linked at carbon atoms.

The term “guanidine”, as used herein, alone or in combination, refers to—NHC(═NH)NH₂, or the corresponding guanidinium cation.

The term “halo,” or “halogen,” as used herein, alone or in combination,refers to fluorine, chlorine, bromine, or iodine.

The term “haloalkoxy,” as used herein, alone or in combination, refersto a haloalkyl group attached to the parent molecular moiety through anoxygen atom.

The term “haloalkyl,” as used herein, alone or in combination, refers toan alkyl group having the meaning as defined above wherein one or morehydrogen atoms are replaced with a halogen. Specifically embraced aremonohaloalkyl, dihaloalkyl and polyhaloalkyl groups. A monohaloalkylgroup, for one example, may have an iodo, bromo, chloro or fluoro atomwithin the group. Dihalo and polyhaloalkyl groups may have two or moreof the same halo atoms or a combination of different halo groups.Examples of haloalkyl groups include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. “Haloalkylene” refers to a haloalkyl group attached attwo or more positions. Examples include fluoromethylene (—CFH—),difluoromethylene (—CF₂—), chloromethylene (—CHCl—) and the like.

The term “heteroalkyl,” as used herein, alone or in combination, refersto a stable straight or branched chain, or cyclic hydrocarbon group, orcombinations thereof, fully saturated or containing from 1 to 3 degreesof unsaturation, consisting of the stated number of carbon atoms andfrom one to three heteroatoms chosen from O, N, and S, and wherein thenitrogen and sulfur atoms may optionally be oxidized and the nitrogenheteroatom may optionally be quaternized. The heteroatom(s) O, N and Smay be placed at any interior position of the heteroalkyl group. Up totwo heteroatoms may be consecutive, such as, for example, —CH₂—NH—OCH₃.

The term “heteroaryl,” as used herein, alone or in combination, refersto a 3 to 7 membered unsaturated heteromonocyclic ring, or a fusedmonocyclic, bicyclic, or tricyclic ring system in which at least one ofthe fused rings is aromatic, which contains at least one atom chosenfrom B, O, S, and N. In certain embodiments, said heteroaryl willcomprise from 5 to 7 carbon atoms. The term also embraces fusedpolycyclic groups wherein heterocyclic rings are fused with aryl rings,wherein heteroaryl rings are fused with other heteroaryl rings, whereinheteroaryl rings are fused with heterocycloalkyl rings, or whereinheteroaryl rings are fused with cycloalkyl rings. Examples of heteroarylgroups include pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, triazolyl, pyranyl, furyl, thienyl,oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, thiadiazolyl,isothiazolyl, indolyl, isoindolyl, indolizinyl, benzimidazolyl,quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, indazolyl,benzoxaborole, benzotriazolyl, benzodioxolyl, benzopyranyl,benzoxazolyl, benzoxadiazolyl, benzothiazolyl, benzothiadiazolyl,benzofuryl, benzothienyl, chromonyl, coumarinyl, benzopyranyl,tetrahydroquinolinyl, tetrazolopyridazinyl, tetrahydroisoquinolinyl,thienopyridinyl, furopyridinyl, pyrrolopyridinyl and the like. Exemplarytricyclic heterocyclic groups include carbazolyl, benzidolyl,phenanthrolinyl, dibenzofuranyl, acridinyl, phenanthridinyl, xanthenyland the like.

The terms “heterocycloalkyl” and, interchangeably, “heterocycle,” asused herein, alone or in combination, each refer to a saturated,partially unsaturated, or fully unsaturated monocyclic, bicyclic, ortricyclic heterocyclic group containing at least one heteroatom as aring member, wherein each said heteroatom may be independently chosenfrom nitrogen, oxygen, and sulfur In certain embodiments, saidhetercycloalkyl will comprise from 1 to 4 heteroatoms as ring members.In further embodiments, said hetercycloalkyl will comprise from 1 to 2heteroatoms as ring members. In certain embodiments, saidhetercycloalkyl will comprise from 3 to 8 ring members in each ring. Infurther embodiments, said hetercycloalkyl will comprise from 3 to 7 ringmembers in each ring. In yet further embodiments, said hetercycloalkylwill comprise from 5 to 6 ring members in each ring. “Heterocycloalkyl”and “heterocycle” are intended to include sulfones, sulfoxides, N-oxidesof tertiary nitrogen ring members, and carbocyclic fused and benzo fusedring systems; additionally, both terms also include systems where aheterocycle ring is fused to an aryl group, as defined herein, or anadditional heterocycle group. Examples of heterocycle groups includeaziridinyl, azetidinyl, 1,3-benzodioxolyl, dihydroisoindolyl,dihydroisoquinolinyl, dihydrocinnolinyl, dihydrobenzodioxinyl,dihydro[1,3]oxazolo[4,5-b]pyridinyl, benzothiazolyl, dihydroindolyl,dihy-dropyridinyl, 1,3-dioxanyl, 1,4-dioxanyl, 1,3-dioxolanyl,isoindolinyl, morpholinyl, piperazinyl, methylpiperazinyl,N-methylpiperazinyl, pyrrolidinyl, tetrahydropyridinyl, piperidinyl,thiomorpholinyl, diazepanyl, and the like. The heterocycle groups may beoptionally substituted unless specifically prohibited.

The term “hydrazinyl” as used herein, alone or in combination, refers totwo amino groups joined by a single bond, i.e., —N—N—.

The term “hydroxy,” as used herein, alone or in combination, refers to—OH.

The term “hydroxyalkyl,” as used herein, alone or in combination, refersto a hydroxy group attached to the parent molecular moiety through analkyl group.

The term “hydroxamic acid”, as used herein, alone or in combination,refers to —C(═O)NHOH, wherein the parent molecular moiety is attached tothe hydroxamic acid group by means of the carbon atom.

The term “imino,” as used herein, alone or in combination, refers to═N—.

The term “iminohydroxy,” as used herein, alone or in combination, refersto ═N(OH) and ═N—O—.

The phrase “the main chain” refers to the longest contiguous or adjacentchain of carbon atoms starting at the point of attachment of a group tothe compounds of any one of the formulas disclosed herein.

The phrase “linear chain of atoms” refers to the longest straight chainof atoms independently selected from carbon, nitrogen, oxygen andsulfur.

The term “lower,” as used herein, alone or in a combination, where nototherwise specifically defined, means containing from 1 to and including6 carbon atoms. Lower alkyl may not be cyclic.

The term “lower heteroalkyl,” as used herein, alone or in combination,means an alkyl chain comprising between one and three heteroatoms chosenfrom O, S, and N, wherein the main chain comprises between two and sixatoms. A heteroatom in a heteroalkyl chain may be substituted asfollows: S may be substituted with zero, one, or two oxy substituents; Nmay be substituted with hydrogen, oxygen, lower alkyl, lower alkoxy, orlower cycloalkyl; and O may be substituted with lower alkyl or lowercycloalkyl.

The term “lower cycloalkyl,” as used herein, alone or in combination,means a monocyclic cycloalkyl having between three and six ring members.Lower cycloalkyls may be unsaturated. Examples of lower cycloalkylinclude cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

The term “lower heterocycloalkyl,” as used herein, alone or incombination, means a monocyclic heterocycloalkyl having between threeand six ring members, of which between one and four may be heteroatomschosen from O, S, and N. Examples of lower heterocycloalkyls includepyrrolidinyl, imidazolidinyl, pyrazolidinyl, piperidinyl, piperazinyl,and morpholinyl. Lower heterocycloalkyls may be unsaturated.

The term “nitro,” as used herein, alone or in combination, refers to—NO₂.

The terms “oxy” or “oxa,” as used herein, alone or in combination, referto —O—.

The term “oxo,” as used herein, alone or in combination, refers to ═O.

The term “perhaloalkoxy” refers to an alkoxy group where all of thehydrogen atoms are replaced by halogen atoms.

The term “perhaloalkyl” as used herein, alone or in combination, refersto an alkyl group where all of the hydrogen atoms are replaced byhalogen atoms.

The term “phosphonate,” as used herein, alone or in combination, refersto a —P(═O)(OR)₂ group, wherein R is chosen from alkyl and aryl. Theterm “phosphonic acid”, as used herein, alone or in combination, refersto a —P(═O)(OH)₂ group.

The terms “sulfonate,” “sulfonic acid,” and “sulfonic,” as used herein,alone or in combination, refer to the —SO₃H group and its anion as thesulfonic acid is used in salt formation.

The term “sulfanyl,” as used herein, alone or in combination, refers to—S—.

The term “sulfinyl,” as used herein, alone or in combination, refers to—S(O)—.

The term “sulfonyl,” as used herein, alone or in combination, refers to—S(O)₂—.

The term “N-sulfonamido” refers to a RS(O)₂NR′— group with R and R′ asdefined herein.

The term “S-sulfonamido” refers to a —S(O)₂NRR′, group, with R and R′ asdefined herein.

The terms “thia” and “thio,” as used herein, alone or in combination,refer to a —S— group or an ether wherein the oxygen is replaced withsulfur. The oxidized derivatives of the thio group, namely sulfinyl andsulfonyl, are included in the definition of thia and thio.

The term “thiol,” as used herein, alone or in combination, refers to an—SH group.

The term “trihalomethoxy” refers to a X₃CO— group where X is a halogen.

Any definition herein may be used in combination with any otherdefinition to describe a composite structural group. By convention, thetrailing element of any such definition is that which attaches to theparent moiety. For example, the composite group alkylamido wouldrepresent an alkyl group attached to the parent molecule through anamido group, and the term alkoxyalkyl would represent an alkoxy groupattached to the parent molecule through an alkyl group.

When a group is defined to be “null,” what is meant is that said groupis absent. When any one or more of G¹, G², and G³ of —(CH₂)_(s)G¹G²G³ isdesignated to be “null”, said group condenses to either a bond if itoccupies an interior position (as with G¹ and G²), or is absent if itoccupies a terminal position (as with G³). Thus, for example, if G¹ andG³ are both null, then —(CH₂)_(s)G¹G²G³ condenses to —(CH₂)_(s)G². If G²and G³ are both null, then —(CH₂)_(s)G¹G²G³ condenses to —(CH₂)_(s)G¹.Similarly, if G¹ and G² are both null, then —(CH₂)_(s)G¹G²G³ condensesto —(CH₂)_(s)G³. When s is designated to be 0, then the (CH₂)_(s)portion of —(CH₂)_(s)G¹G²G³ collapses to a bond connecting O to G¹G²G³.Each of G¹, G², and G³ are not meant to be null simultaneously and onlytwo of G¹, G², and G³ may be null at once.

The term “optionally substituted” means the anteceding group may besubstituted or unsubstituted. When substituted, the substituents of an“optionally substituted” group may include, without limitation, one ormore substituents independently selected from the following groups or aparticular designated set of groups, alone or in combination: loweralkyl, lower alkenyl, lower alkynyl, lower alkanoyl, lower heteroalkyl,lower heterocycloalkyl, lower haloalkyl, lower haloalkenyl, lowerhaloalkynyl, lower perhaloalkyl, lower perhaloalkoxy, lower cycloalkyl,phenyl, aryl, aryloxy, lower alkoxy, lower haloalkoxy, oxo, loweracyloxy, carbonyl, carboxyl, lower alkylcarbonyl, lower carboxyester,lower carboxamido, cyano, hydrogen, halogen, hydroxy, amino, loweralkylamino, arylamino, amido, nitro, thiol, lower alkylthio, lowerhaloalkylthio, lower perhaloalkylthio, arylthio, sulfonate, sulfonicacid, trisubstituted silyl, N₃, SH, SCH₃, C(O)CH₃, CO₂CH₃, CO₂H,pyridinyl, thiophene, furanyl, lower carbamate, and lower urea. Twosubstituents may be joined together to form a fused five-, six-, orseven-membered carbocyclic or heterocyclic ring consisting of zero tothree heteroatoms, for example forming methylenedioxy or ethylenedioxy.An optionally substituted group may be unsubstituted (e.g., —CH₂CH₃),fully substituted (e.g., —CF₂CF₃), monosubstituted (e.g., —CH₂CH₂F) orsubstituted at a level anywhere in-between fully substituted andmonosubstituted (e.g., —CH₂CF₃). Where substituents are recited withoutqualification as to substitution, both substituted and unsubstitutedforms are encompassed. Where a substituent is qualified as“substituted,” the substituted form is specifically intended.Additionally, different sets of optional substituents to a particularmoiety may be defined as needed; in these cases, the optionalsubstitution will be as defined, often immediately following the phrase,“optionally substituted with.”

The term R or the term R′, appearing by itself and without a numberdesignation, unless otherwise defined, refers to a moiety chosen fromhydrogen, alkyl, cycloalkyl, heteroalkyl, aryl, heteroaryl andheterocycloalkyl, any of which may be optionally substituted. Such R andR′ groups should be understood to be optionally substituted as definedherein. Whether an R group has a number designation or not, every Rgroup, including R, R′ and R^(n) where n=(1, 2, 3, . . . n), everysubstituent, and every term should be understood to be independent ofevery other in terms of selection from a group. Should any variable,substituent, or term (e.g. aryl, heterocycle, R, etc.) occur more thanone time in a formula or generic structure, its definition at eachoccurrence is independent of the definition at every other occurrence.Those of skill in the art will further recognize that certain groups maybe attached to a parent molecule or may occupy a position in a chain ofelements from either end as written. Thus, by way of example only, anunsymmetrical group such as —C(O)N(R)— may be attached to the parentmoiety at either the carbon or the nitrogen.

Asymmetric centers exist in the compounds disclosed herein. Thesecenters are designated by the symbols “R” or “S,” depending on theconfiguration of substituents around the chiral carbon atom. It shouldbe understood that the invention encompasses all stereochemical isomericforms, including diastereomeric, enantiomeric, and epimeric forms, aswell as d-isomers and 1-isomers, and mixtures thereof. Individualstereoisomers of compounds can be prepared synthetically fromcommercially available starting materials which contain chiral centersor by preparation of mixtures of enantiomeric products followed byseparation such as conversion to a mixture of diastereomers followed byseparation or recrystallization, chromatographic techniques, directseparation of enantiomers on chiral chromatographic columns, or anyother appropriate method known in the art. Starting compounds ofparticular stereochemistry are either commercially available or can bemade and resolved by techniques known in the art. Additionally, thecompounds disclosed herein may exist as geometric isomers. The presentinvention includes all cis, trans, syn, anti, entgegen (E), and zusammen(Z) isomers as well as the appropriate mixtures thereof. Additionally,compounds may exist as tautomers; all tautomeric isomers are provided bythis invention. Additionally, the compounds disclosed herein can existin unsolvated as well as solvated forms with pharmaceutically acceptablesolvents such as water, ethanol, and the like. In general, the solvatedforms are considered equivalent to the unsolvated forms.

The term “bond” refers to a covalent linkage between two atoms, or twomoieties when the atoms joined by the bond are considered to be part oflarger substructure. A bond may be single, double, or triple unlessotherwise specified. A combination of a straight and a dashed lineparallel between two atoms in a drawing of a molecule indicates that anadditional bond may be present or absent at that position; a dashed bondalone, bisected by a wavy line, indicates that the structure depicted isconnected to another structure, not shown.

The term “disease” as used herein is intended to be generallysynonymous, and is used interchangeably with, the terms “disorder” and“condition” (as in medical condition), in that all reflect an abnormalcondition of the human or animal body or of one of its parts thatimpairs normal functioning, is typically manifested by distinguishingsigns and symptoms, and causes the human or animal to have a reducedduration or quality of life.

The term “combination therapy” means the administration of two or moretherapeutic agents to treat a therapeutic condition or disorderdescribed in the present disclosure. Such administration encompassesco-administration of these therapeutic agents in a substantiallysimultaneous manner, such as in a single capsule having a fixed ratio ofactive ingredients or in multiple, separate capsules for each activeingredient. In addition, such administration also encompasses use ofeach type of therapeutic agent in a sequential manner. In either case,the treatment regimen will provide beneficial effects of the drugcombination in treating the conditions or disorders described herein.

“PDE4 inhibitor” is used herein to refer to a compound that exhibits anIC₅₀ with respect to PDE4 activity of no more than about 100 μM and moretypically not more than about 50 μM, as measured in the PDE4 assaydescribed generally hereinbelow. “IC₅₀” is that concentration ofinhibitor which reduces the activity of an enzyme (e.g., PDE4) tohalf-maximal level. Certain representative compounds of the presentinvention have been discovered to exhibit inhibition against PDE4. Incertain embodiments, compounds will exhibit an IC₅₀ with respect to PDE4of no more than about 10 μM; in further embodiments, compounds willexhibit an IC₅₀ with respect to PDE4 of no more than about 5 μM; in yetfurther embodiments, compounds will exhibit an IC₅₀ with respect to PDE4of not more than about 1 μM, as measured in the PDE4 assay describedherein. In yet further embodiments, compounds will exhibit an IC₅₀ withrespect to PDE4 of not more than about 200 nM.

The phrase “therapeutically effective” is intended to qualify the amountof active ingredients used in the treatment of a disease or disorder.This amount will achieve the goal of reducing or eliminating the saiddisease or disorder.

The term “therapeutically acceptable” refers to those compounds (orsalts, prodrugs, tautomers, zwitterionic forms, etc.) which are suitablefor use in contact with the tissues of patients without undue toxicity,irritation, and allergic response, are commensurate with a reasonablebenefit/risk ratio, and are effective for their intended use.

As used herein, reference to “treatment” of a patient is intended toinclude prophylaxis. The term “patient” means all mammals includinghumans. Examples of patients include humans, cows, dogs, cats, goats,sheep, pigs, and rabbits. Preferably, the patient is a human.

The term “prodrug” refers to a compound that is made more active invivo. Certain compounds disclosed herein may also exist as prodrugs, asdescribed in Hydrolysis in Drug and Prodrug Metabolism: Chemistry,Biochemistry, and Enzymology (Testa, Bernard and Mayer, Joachim M.Wiley-VHCA, Zurich, Switzerland 2003). Prodrugs of the compoundsdescribed herein are structurally modified forms of the compound thatreadily undergo chemical changes under physiological conditions toprovide the compound. Additionally, prodrugs can be converted to thecompound by chemical or biochemical methods in an ex vivo environment.For example, prodrugs can be slowly converted to a compound when placedin a transdermal patch reservoir with a suitable enzyme or chemicalreagent. Prodrugs are often useful because, in some situations, they maybe easier to administer than the compound, or parent drug. They may, forinstance, be bioavailable by oral administration whereas the parent drugis not. The prodrug may also have improved solubility in pharmaceuticalcompositions over the parent drug. A wide variety of prodrug derivativesare known in the art, such as those that rely on hydrolytic cleavage oroxidative activation of the prodrug. An example, without limitation, ofa prodrug would be a compound which is administered as an ester (the“prodrug”), but then is metabolically hydrolyzed to the carboxylic acid,the active entity. Additional examples include peptidyl derivatives of acompound.

The compounds disclosed herein can exist as therapeutically acceptablesalts. The present invention includes compounds listed above in the formof salts, including acid addition salts. Suitable salts include thoseformed with both organic and inorganic acids. Such acid addition saltswill normally be pharmaceutically acceptable. However, salts ofnon-pharmaceutically acceptable salts may be of utility in thepreparation and purification of the compound in question. Basic additionsalts may also be formed and be pharmaceutically acceptable. For a morecomplete discussion of the preparation and selection of salts, refer toPharmaceutical Salts: Properties, Selection, and Use (Stahl, P.Heinrich. Wiley-VCHA, Zurich, Switzerland, 2002).

The term “therapeutically acceptable salt,” as used herein, representssalts or zwitterionic forms of the compounds disclosed herein which arewater or oil-soluble or dispersible and therapeutically acceptable asdefined herein. The salts can be prepared during the final isolation andpurification of the compounds or separately by reacting the appropriatecompound in the form of the free base with a suitable acid.Representative acid addition salts include acetate, adipate, alginate,L-ascorbate, aspartate, benzoate, benzenesulfonate (besylate),bisulfate, butyrate, camphorate, camphorsulfonate, citrate, digluconate,formate, fumarate, gentisate, glutarate, glycerophosphate, glycolate,hemisulfate, heptanoate, hexanoate, hippurate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate),lactate, maleate, malonate, DL-mandelate, mesitylenesulfonate,methanesulfonate, naphthylenesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylproprionate, phosphonate, picrate, pivalate, propionate,pyroglutamate, succinate, sulfonate, tartrate, L-tartrate,trichloroacetate, trifluoroacetate, phosphate, glutamate, bicarbonate,para-toluenesulfonate (p-tosylate), and undecanoate. Also, basic groupsin the compounds disclosed herein can be quaternized with methyl, ethyl,propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl,dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and sterylchlorides, bromides, and iodides; and benzyl and phenethyl bromides.Examples of acids which can be employed to form therapeuticallyacceptable addition salts include inorganic acids such as hydrochloric,hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic,maleic, succinic, and citric. Salts can also be formed by coordinationof the compounds with an alkali metal or alkaline earth ion. Hence, thepresent invention contemplates sodium, potassium, magnesium, and calciumsalts of the compounds disclosed herein, and the like.

Basic addition salts can be prepared during the final isolation andpurification of the compounds by reaction of a carboxy group with asuitable base such as the hydroxide, carbonate, or bicarbonate of ametal cation or with ammonia or an organic primary, secondary, ortertiary amine. The cations of therapeutically acceptable salts includelithium, sodium, potassium, calcium, magnesium, and aluminum, as well asnontoxic quaternary amine cations such as ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine,1-ephenamine, and N,N-dibenzylethylenediamine. Other representativeorganic amines useful for the formation of base addition salts includeethylenediamine, ethanolamine, diethanolamine, piperidine, andpiperazine.

A salt of a compound can be made by reaction of the appropriatecompound, in the form of the free base, with the appropriate acid.

While it may be possible for the compounds of the subject invention tobe administered as the raw chemical, it is also possible to present themas a pharmaceutical formulation (equivalently, a “pharmaceuticalcomposition”). Accordingly, provided herein are pharmaceuticalformulations which comprise one or more of certain compounds disclosedherein, or one or more pharmaceutically acceptable salts, esters,prodrugs, amides, or solvates thereof, together with one or morepharmaceutically acceptable carriers thereof and optionally one or moreother therapeutic ingredients. The carrier(s) must be “acceptable” inthe sense of being compatible with the other ingredients of theformulation and not deleterious to the recipient thereof. Properformulation is dependent upon the route of administration chosen. Any ofthe well-known techniques, carriers, and excipients may be used assuitable and as understood in the art; e.g., in Remington'sPharmaceutical Sciences. The pharmaceutical compositions disclosedherein may be manufactured in any manner known in the art, e.g., bymeans of conventional mixing, dissolving, granulating, dragee-making,levigating, emulsifying, encapsulating, entrapping or compressionprocesses.

The formulations include those suitable for oral, parenteral (includingsubcutaneous, intradermal, intramuscular, intravenous, intraarticular,and intramedullary), intraperitoneal, transmucosal, transdermal, rectaland topical (including dermal, buccal, sublingual and intraocular)administration although the most suitable route may depend upon forexample the condition and disorder of the recipient. The formulationsmay conveniently be presented in unit dosage form and may be prepared byany of the methods well known in the art of pharmacy. Typically, thesemethods include the step of bringing into association a compound of thesubject invention or a pharmaceutically acceptable salt, ester, amide,prodrug or solvate thereof (“active ingredient”) with the carrier whichconstitutes one or more accessory ingredients. In general, theformulations are prepared by uniformly and intimately bringing intoassociation the active ingredient with liquid carriers or finely dividedsolid carriers or both and then, if necessary, shaping the product intothe desired formulation.

Formulations of the compounds disclosed herein suitable for oraladministration may be presented as discrete units such as capsules,cachets or tablets each containing a predetermined amount of the activeingredient; as a powder or granules; as a solution or a suspension in anaqueous liquid or a non-aqueous liquid; or as an oil-in-water liquidemulsion or a water-in-oil liquid emulsion. The active ingredient mayalso be presented as a bolus, electuary or paste.

Pharmaceutical preparations which can be used orally include tablets,push-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin and a plasticizer, such as glycerol or sorbitol. Tablets maybe made by compression or molding, optionally with one or more accessoryingredients. Compressed tablets may be prepared by compressing in asuitable machine the active ingredient in a free-flowing form such as apowder or granules, optionally mixed with binders, inert diluents, orlubricating, surface active or dispersing agents. Molded tablets may bemade by molding in a suitable machine a mixture of the powdered compoundmoistened with an inert liquid diluent. The tablets may optionally becoated or scored and may be formulated so as to provide slow orcontrolled release of the active ingredient therein. All formulationsfor oral administration should be in dosages suitable for suchadministration. The push-fit capsules can contain the active ingredientsin admixture with filler such as lactose, binders such as starches,and/or lubricants such as talc or magnesium stearate and, optionally,stabilizers. In soft capsules, the active compounds may be dissolved orsuspended in suitable liquids, such as fatty oils, liquid paraffin, orliquid polyethylene glycols. In addition, stabilizers may be added.Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethyleneglycol, and/or titanium dioxide, lacquer solutions, and suitable organicsolvents or solvent mixtures. Dyestuffs or pigments may be added to thetablets or dragee coatings for identification or to characterizedifferent combinations of active compound doses.

The compounds may be formulated for parenteral administration byinjection, e.g., by bolus injection or continuous infusion. Formulationsfor injection may be presented in unit dosage form, e.g., in ampoules orin multi-dose containers, with an added preservative. The compositionsmay take such forms as suspensions, solutions or emulsions in oily oraqueous vehicles, and may contain formulatory agents such as suspending,stabilizing and/or dispersing agents. The formulations may be presentedin unit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in powder form or in a freeze-dried(lyophilized) condition requiring only the addition of the sterileliquid carrier, for example, saline or sterile pyrogen-free water,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tabletsof the kind previously described.

Formulations for parenteral administration include aqueous andnon-aqueous (oily) sterile injection solutions of the active compoundswhich may contain antioxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic with the blood of the intendedrecipient; and aqueous and non-aqueous sterile suspensions which mayinclude suspending agents and thickening agents. Suitable lipophilicsolvents or vehicles include fatty oils such as sesame oil, or syntheticfatty acid esters, such as ethyl oleate or triglycerides, or liposomes.Aqueous injection suspensions may contain substances which increase theviscosity of the suspension, such as sodium carboxymethyl cellulose,sorbitol, or dextran. Optionally, the suspension may also containsuitable stabilizers or agents which increase the solubility of thecompounds to allow for the preparation of highly concentrated solutions.

In addition to the formulations described previously, the compounds mayalso be formulated as a depot preparation. Such long acting formulationsmay be administered by implantation (for example subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds may be formulated with suitable polymeric or hydrophobicmaterials (for example as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

For buccal or sublingual administration, the compositions may take theform of tablets, lozenges, pastilles, or gels formulated in conventionalmanner. Such compositions may comprise the active ingredient in aflavored basis such as sucrose and acacia or tragacanth.

The compounds may also be formulated in rectal compositions such assuppositories or retention enemas, e.g., containing conventionalsuppository bases such as cocoa butter, polyethylene glycol, or otherglycerides.

Certain compounds disclosed herein may be administered topically, thatis by non-systemic administration. This includes the application of acompound disclosed herein externally to the epidermis or the buccalcavity and the instillation of such a compound into the ear, eye andnose, such that the compound does not significantly enter the bloodstream. In contrast, systemic administration refers to oral,intravenous, intraperitoneal and intramuscular administration.

Formulations suitable for topical administration include liquid orsemi-liquid preparations suitable for penetration through the skin tothe site of inflammation such as gels, liniments, lotions, creams,ointments or pastes, and drops suitable for administration to the eye,ear or nose. The active ingredient for topical administration maycomprise, for example, from 0.001% to 10% w/w (by weight) of theformulation. In certain embodiments, the active ingredient may compriseas much as 10% w/w. In other embodiments, it may comprise less than 5%w/w. In certain embodiments, the active ingredient may comprise from 2%w/w to 5% w/w. In other embodiments, it may comprise from 0.1% to 1% w/wof the formulation.

Topical ophthalmic, otic, and nasal formulations of the presentinvention may comprise excipients in addition to the active ingredient.Excipients commonly used in such formulations include, but are notlimited to, tonicity agents, preservatives, chelating agents, bufferingagents, and surfactants. Other excipients comprise solubilizing agents,stabilizing agents, comfort-enhancing agents, polymers, emollients,pH-adjusting agents and/or lubricants. Any of a variety of excipientsmay be used in formulations of the present invention including water,mixtures of water and water-miscible solvents, such as C1-C7-alkanols,vegetable oils or mineral oils comprising from 0.5 to 5% non-toxicwater-soluble polymers, natural products, such as alginates, pectins,tragacanth, karaya gum, guar gum, xanthan gum, carrageenan, agar andacacia, starch derivatives, such as starch acetate and hydroxypropylstarch, and also other synthetic products such as polyvinyl alcohol,polyvinylpyrrolidone, polyvinyl methyl ether, polyethylene oxide,preferably cross-linked polyacrylic acid and mixtures of those products.The concentration of the excipient is, typically, from 1 to 100,000times the concentration of the active ingredient. In preferredembodiments, the excipients to be included in the formulations aretypically selected on the basis of their inertness towards the activeingredient component of the formulations.

Relative to ophthalmic, otic, and nasal formulations, suitabletonicity-adjusting agents include, but are not limited to, mannitol,sodium chloride, glycerin, sorbitol and the like. Suitable bufferingagents include, but are not limited to, phosphates, borates, acetatesand the like. Suitable surfactants include, but are not limited to,ionic and nonionic surfactants (though nonionic surfactants arepreferred), RLM 100, POE 20 cetylstearyl ethers such as PROCOL® CS20 andpoloxamers such as PLURONIC® F68.

The formulations set forth herein may comprise one or morepreservatives. Examples of such preservatives include p-hydroxybenzoicacid ester, sodium perborate, sodium chlorite, alcohols such aschlorobutanol, benzyl alcohol or phenyl ethanol, guanidine derivativessuch as polyhexamethylene biguanide, sodium perborate, polyquaternium-1,amino alcohols such as AMP-95, or sorbic acid. In certain embodiments,the formulation may be self-preserved so that no preservation agent isrequired.

For ophthalmic, otic, or nasal administration, the formulation may be asolution, a suspension, or a gel. In preferred aspects, the formulationsare for topical application to the eye, nose, or ear in aqueous solutionin the form of drops. The term “aqueous” typically denotes an aqueousformulation wherein the formulation is >50%, more preferably >75% and inparticular >90% by weight water. These drops may be delivered from asingle dose ampoule which may preferably be sterile and thus renderbacteriostatic components of the formulation unnecessary. Alternatively,the drops may be delivered from a multi-dose bottle which may preferablycomprise a device which extracts any preservative from the formulationas it is delivered, such devices being known in the art.

For ophthalmic disorders, components of the invention may be deliveredto the eye as a concentrated gel or a similar vehicle, or as dissolvableinserts that are placed beneath the eyelids.

The formulations of the present invention that are adapted for topicaladministration to the eye are preferably isotonic, or slightly hypotonicin order to combat any hypertonicity of tears caused by evaporationand/or disease. This may require a tonicity agent to bring theosmolality of the formulation to a level at or near 210-320 milliosmolesper kilogram (mOsm/kg). The formulations of the present inventiongenerally have an osmolality in the range of 220-320 mOsm/kg, andpreferably have an osmolality in the range of 235-300 mOsm/kg. Theophthalmic formulations will generally be formulated as sterile aqueoussolutions.

In certain ophthalmic embodiments, the compositions of the presentinvention are formulated with one or more tear substitutes. A variety oftear substitutes are known in the art and include, but are not limitedto: monomeric polyols, such as, glycerol, propylene glycol, and ethyleneglycol; polymeric polyols such as polyethylene glycol; cellulose esterssuch hydroxypropylmethyl cellulose, carboxy methylcellulose sodium andhydroxy propylcellulose; dextrans such as dextran 70; vinyl polymers,such as polyvinyl alcohol; and carbomers, such as carbomer 934P,carbomer 941, carbomer 940 and carbomer 974P. Certain formulations ofthe present invention may be used with contact lenses or otherophthalmic products.

In certain embodiments, formulations are prepared using a bufferingsystem that maintains the formulation at a pH of about 4.5 to a pH ofabout 8. A most preferred formulation pH is from 7 to 8.

In certain embodiments, a formulation of the present invention isadministered once a day. However, the formulations may also beformulated for administration at any frequency of administration,including once a week, once every 5 days, once every 3 days, once every2 days, twice a day, three times a day, four times a day, five times aday, six times a day, eight times a day, every hour, or any greaterfrequency. Such dosing frequency is also maintained for a varyingduration of time depending on the therapeutic regimen. The duration of aparticular therapeutic regimen may vary from one-time dosing to aregimen that extends for months or years. The formulations areadministered at varying dosages, but typical dosages are one to twodrops at each administration, or a comparable amount of a gel or otherformulation. One of ordinary skill in the art would be familiar withdetermining a therapeutic regimen for a specific indication.

Gels for topical or transdermal administration may comprise, generally,a mixture of volatile solvents, nonvolatile solvents, and water. Incertain embodiments, the volatile solvent component of the bufferedsolvent system may include lower (C1-C6) alkyl alcohols, lower alkylglycols and lower glycol polymers. In further embodiments, the volatilesolvent is ethanol. The volatile solvent component is thought to act asa penetration enhancer, while also producing a cooling effect on theskin as it evaporates. The nonvolatile solvent portion of the bufferedsolvent system is selected from lower alkylene glycols and lower glycolpolymers. In certain embodiments, propylene glycol is used. Thenonvolatile solvent slows the evaporation of the volatile solvent andreduces the vapor pressure of the buffered solvent system. The amount ofthis nonvolatile solvent component, as with the volatile solvent, isdetermined by the pharmaceutical compound or drug being used. When toolittle of the nonvolatile solvent is in the system, the pharmaceuticalcompound may crystallize due to evaporation of volatile solvent, whilean excess may result in a lack of bioavailability due to poor release ofdrug from solvent mixture. The buffer component of the buffered solventsystem may be selected from any buffer commonly used in the art; incertain embodiments, water is used. A common ratio of ingredients isabout 20% of the nonvolatile solvent, about 40% of the volatile solvent,and about 40% water. There are several optional ingredients which can beadded to the topical composition. These include, but are not limited to,chelators and gelling agents. Appropriate gelling agents can include,but are not limited to, semisynthetic cellulose derivatives (such ashydroxypropylmethylcellulose) and synthetic polymers, galactomannanpolymers (such as guar and derivatives thereof), and cosmetic agents.

Lotions include those suitable for application to the skin or eye. Aneye lotion may comprise a sterile aqueous solution optionally containinga bactericide and may be prepared by methods similar to those for thepreparation of drops. Lotions or liniments for application to the skinmay also include an agent to hasten drying and to cool the skin, such asan alcohol or acetone, and/or a moisturizer such as glycerol or an oilsuch as castor oil or arachis oil.

Creams, ointments or pastes are semi-solid formulations of the activeingredient for external application. They may be made by mixing theactive ingredient in finely-divided or powdered form, alone or insolution or suspension in an aqueous or non-aqueous fluid, with the aidof suitable machinery, with a greasy or non-greasy base. The base maycomprise hydrocarbons such as hard, soft or liquid paraffin, glycerol,beeswax, a metallic soap; a mucilage; an oil of natural origin such asalmond, corn, arachis, castor or olive oil; wool fat or its derivativesor a fatty acid such as steric or oleic acid together with an alcoholsuch as propylene glycol or a macrogel. The formulation may incorporateany suitable surface active agent such as an anionic, cationic ornon-ionic surfactant such as a sorbitan ester or a polyoxyethylenederivative thereof. Suspending agents such as natural gums, cellulosederivatives or inorganic materials such as silicaceous silicas, andother ingredients such as lanolin, may also be included.

Drops may comprise sterile aqueous or oily solutions or suspensions andmay be prepared by dissolving the active ingredient in a suitableaqueous solution of a bactericidal and/or fungicidal agent and/or anyother suitable preservative, and, in certain embodiments, including asurface active agent. The resulting solution may then be clarified byfiltration, transferred to a suitable container which is then sealed andsterilized by autoclaving or maintaining at 98-100° C. for half an hour.Alternatively, the solution may be sterilized by filtration andtransferred to the container by an aseptic technique. Examples ofbactericidal and fungicidal agents suitable for inclusion in the dropsare phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride(0.01%) and chlorhexidine acetate (0.01%). Suitable solvents for thepreparation of an oily solution include glycerol, diluted alcohol andpropylene glycol.

Formulations for topical administration in the mouth, for examplebuccally or sublingually, include lozenges comprising the activeingredient in a flavored basis such as sucrose and acacia or tragacanth,and pastilles comprising the active ingredient in a basis such asgelatin and glycerin or sucrose and acacia.

For administration by inhalation, compounds may be convenientlydelivered from an insufflator, nebulizer pressurized packs or otherconvenient means of delivering an aerosol spray. Pressurized packs maycomprise a suitable propellant such as dichlorodifluoromethane,trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide orother suitable gas. In the case of a pressurized aerosol, the dosageunit may be determined by providing a valve to deliver a metered amount.Alternatively, for administration by inhalation or insufflation, thecompounds according to the invention may take the form of a dry powdercomposition, for example a powder mix of the compound and a suitablepowder base such as lactose or starch. The powder composition may bepresented in unit dosage form, in for example, capsules, cartridges,gelatin or blister packs from which the powder may be administered withthe aid of an inhalator or insufflator.

Preferred unit dosage formulations are those containing an effectivedose, as herein below recited, or an appropriate fraction thereof, ofthe active ingredient.

It should be understood that in addition to the ingredients particularlymentioned above, the formulations described above may include otheragents conventional in the art having regard to the type of formulationin question, for example those suitable for oral administration mayinclude flavoring agents.

Compounds may be administered orally or via injection at a dose of from0.1 to 500 mg/kg per day. The dose range for adult humans is generallyfrom 5 mg to 2 g/day. Tablets or other forms of presentation provided indiscrete units may conveniently contain an amount of one or morecompounds which is effective at such dosage or as a multiple of thesame, for instance, units containing 5 mg to 500 mg, usually around 10mg to 200 mg.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

The compounds can be administered in various modes, e.g. orally,topically, or by injection. The precise amount of compound administeredto a patient will be the responsibility of the attendant physician. Thespecific dose level for any particular patient will depend upon avariety of factors including the activity of the specific compoundemployed, the age, body weight, general health, sex, diets, time ofadministration, route of administration, rate of excretion, drugcombination, the precise disorder being treated, and the severity of theindication or condition being treated. Also, the route of administrationmay vary depending on the condition and its severity.

In certain instances, it may be appropriate to administer at least oneof the compounds described herein (or a pharmaceutically acceptablesalt, ester, or prodrug thereof) in combination with another therapeuticagent. By way of example only, if one of the side effects experienced bya patient upon receiving one of the compounds herein is hypertension,then it may be appropriate to administer an anti-hypertensive agent incombination with the initial therapeutic agent. Or, by way of exampleonly, the therapeutic effectiveness of one of the compounds describedherein may be enhanced by administration of an adjuvant (i.e., by itselfthe adjuvant may only have minimal therapeutic benefit, but incombination with another therapeutic agent, the overall therapeuticbenefit to the patient is enhanced). Or, by way of example only, thebenefit of experienced by a patient may be increased by administeringone of the compounds described herein with another therapeutic agent(which also includes a therapeutic regimen) that also has therapeuticbenefit. By way of example only, in a treatment for diabetes involvingadministration of one of the compounds described herein, increasedtherapeutic benefit may result by also providing the patient withanother therapeutic agent for diabetes. In any case, regardless of thedisease, disorder or condition being treated, the overall benefitexperienced by the patient may simply be additive of the two therapeuticagents or the patient may experience a synergistic benefit.

Specific, non-limiting examples of possible combination therapiesinclude use of the compounds of the invention with anti-nauseamedications (for example, odansetron), antidepressants, nootropics,anti-acetylcholinesterases, N-methyl D-aspartate (NMDA) receptorantagonists, amyloid beta therapeutics, and tau therapeutics,neurotrophic growth factors, cell based therapies and other regenerativemedicine therapies for treatment of neurodegenerative diseases, amongstother therapies which will be apparent to one skilled in the art.

Antidepressants include, for example:

-   -   selective serotonin reuptake inhibitors (SSRIs), such as        citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine,        paroxetine, and sertraline;    -   serotonin-norepinephrine reuptake inhibitors (SNRIs), such as        venlafaxine, desvenlafaxine, minalcipran, levominalcipran,        duloxetine, sibutramine, and bicifadine;    -   noradrenergic and specific serotonergic antidepressants        (NaSSAs), such as mianserin, mirtazepine, esmirtazepine, and        setiptiline;    -   norepinephrine reuptake inhibitors (NRIs), such asatomoxetine,        mazindol, reboxetine, esreboxetine, viloxazine, and other        specific and nonspecific agents which prevent or mitigate        reuptake of norepinephrine (e.g., SNRIs, NDRIs);    -   norepinephrine-dopamine reuptake inhibitors (NDRIs), such as        buproprion;    -   selective serotonin reuptake enhancers, such as tianeptine and        amineptine;    -   norepinephrine-dopamine disinhibitors (NDDIs), such agomelatine;    -   tricyclic antidepressants, including tertiary and secondary        amine varieties, such as amitriptyline, clomipramine, doxepin,        imipramine, trimipramine, desipramine, nortriptyline, and        protriptyline; and    -   monoamine oxidase inhibitors (MAOIs), such as isocarboxazid,        moclobemide, phenelzine, selegiline, and tranylcyrpomine.

Nootropic drugs, also known as cognition enhancers, include stimulants,dopaminergics, cholinergics, serotonergics, and many of theantidepressants listed above, as well as certain natural products (e.g.,caffeine, tryptophan, 5-HTP, nicotine).

-   -   racetams such as piracetam, pramiracetam, oxiracetam, and        aniracetam    -   amphetamine analogues such as amphetamine (Adderall, Dexedrine),        lisdexamfetamine, and methamphetamine;    -   wakefulness enhancers such as modafinil;    -   dopamine reuptake inhibitors such as methylphenidate, and        possibly modafinil;    -   acetylcholinesterase inhibitors used to treat Alzheimer's        disease such as tacrine, donepezil, galantamine, rivastigmine;    -   NMDA receptor antagonists such as memantine;    -   Selective 5-HT6 receptor antagonists such as Lu AE58054;    -   Nicotinic alpha-7 receptor agonists such as EVP-6124;

Amyloid beta (a-beta or αβ) therapies and tau therapies target thepathological accumulation of a-beta and tau proteins associated withneurodegenerative diseases such as Alzheimer's disease and progressivesupernuclear palsy, respectively. A-beta therapies include β-secretaseinhibitors, γ-secretase inhibitors, Aβ₄₂-lowering agents (e.g.tarenflurbil), anti-aggregation agents (e.g. apomorphine), antibodiesand other immunotherapies. Tau therapies include Tau phosphorylationinhibitors, tau fibrillization inhibitors, and tau degradationenhancers.

In any case, the multiple therapeutic agents (at least one of which is acompound disclosed herein) may be administered in any order or evensimultaneously. If simultaneously, the multiple therapeutic agents maybe provided in a single, unified form, or in multiple forms (by way ofexample only, either as a single pill or as two separate pills). One ofthe therapeutic agents may be given in multiple doses, or both may begiven as multiple doses. If not simultaneous, the timing between themultiple doses may be any duration of time ranging from a few minutes tofour weeks.

Thus, in another aspect, the present invention provides methods fortreating PDE4-mediated disorders in a human or animal subject in need ofsuch treatment comprising administering to said subject an amount of acompound of the present invention effective to reduce or prevent saiddisorder in the subject in combination with at least one additionalagent for the treatment of said disorder that is known in the art. In arelated aspect, the present invention provides therapeutic compositionscomprising at least one compound of the present invention in combinationwith one or more additional agents for the treatment of PDE4-mediateddisorders.

The compounds of the subject invention may also be useful for thetreatment of certain diseases and disorders of the nervous system.Central nervous system disorders in which PDE4 inhibition may be usefulinclude cortical dementias including Alzheimer's disease, AIDS-relateddementia (HIV dementia), and mild cognitive impairment (MCI).Neurodegenerative disorders in which PDE4 inhibition may be usefulinclude nerve degeneration or nerve necrosis in disorders such ashypoxia, hypoglycemia, epilepsy, and in cases of central nervous system(CNS) trauma (such as spinal cord and head injury), hyperbaric oxygenconvulsions and toxicity, dementia e.g. pre-senile dementia, andHIV-associated neurodegenerative disorder (HAND), cachexia, Sydenham'schorea, Huntington's disease, Parkinson's Disease, amyotrophic lateralsclerosis (ALS), Korsakoff's syndrome, and impairment relating to acerebral vessel disorder. Further disorders in which PDE4 inhibitionmight prove useful include neuropathies of the central and peripheralnervous system, including, for example, IgA neuropathy, membranousneuropathy, idiopathic neuropathy, drug-induced peripheral neuropathy,diabetic neuropathy, HIV-associated neuropathy, and chronic inflammatorydemyelinating polyneuropathy; as well as transverse myelitis,Guillain-Barré disease, encephalitis, and cancers of the nervous system.Compounds disclosed herein may also be used in the treatment ofpsychological disorders including anxiety, depression, major depressivedisorder (MDD), bipolar disorder, and post-traumatic stress disorder.Compounds disclosed herein may also be used in the treatment of nervoussystem damage, for example that resulting from stroke, ischemiasincluding cerebral ischemia (both focal ischemia, thrombotic stroke andglobal ischemia, for example, secondary to cardiac arrest and ischemicheart disease) and ischemia/reperfusion, ototoxicity and hearing loss,acute insults to the inner ear, including acoustic trauma, blast noise(for example, as experienced by military personnel), exposure toototoxic chemotherapeutic agents for cancer therapy (such as cisplatin)and treatment with aminoglycoside antibiotics and other nervous systemtrauma.

Compounds disclosed herein may also be used in the treatment oftraumatic brain injury (TBI), spinal cord injury (SCI), or a symptomthereof. In certain embodiments, a selective PDE4 B inhibitor asdisclosed herein will be used to treat SCI, in an amount sufficient tocause a detectable improvement in one or more symptoms, or a reductionin the progression of one or more symptoms of SCI. Additionally, theselective PDE4 B inhibitor can be administered in combination withtransplantation into the spinal cord of cells. Contemplated cellsinclude stem cells and glial (e.g., Schwann) cells.

Furthermore, compounds of the subject invention may be used in thetreatment or prevention of opiate tolerance in patients needingprotracted opiate analgesics, and benzodiazepine tolerance in patientstaking benzodiazepines, and other addictive behavior, for example,nicotine addiction, alcoholism, and eating disorders. Moreover, thecompounds and methods of the present invention may be useful in thetreatment or prevention of drug withdrawal symptoms, for exampletreatment or prevention of symptoms of withdrawal from opiate, alcohol,or tobacco addiction.

Compounds disclosed herein may also be used in the treatment of acuteand chronic pain and inflammation. The compounds of the presentinvention may be useful to treat patients with neuropathy, neuropathicpain, or inflammatory pain such as reflex sympatheticdystrophy/causalgia (nerve injury), peripheral neuropathy (includingdiabetic neuropathy), intractable cancer pain, complex regional painsyndrome, and entrapment neuropathy (carpel tunnel syndrome). Thecompounds may also be useful in the treatment of pain associated withacute herpes zoster (shingles), postherpetic neuralgia (PHN), andassociated pain syndromes such as ocular pain. The compounds may furtherbe useful as analgesics in the treatment of pain such as surgicalanalgesia, or as an antipyretic for the treatment of fever. Painindications include, but are not limited to, post-surgical pain forvarious surgical procedures including post-cardiac surgery, dentalpain/dental extraction, pain resulting from cancer, muscular pain,mastalgia, pain resulting from dermal injuries, lower back pain,headaches of various etiologies, including migraine, and the like. Thecompounds may also be useful for the treatment of pain-related disorderssuch as tactile allodynia and hyperalgesia. The pain may be somatogenic(either nociceptive or neuropathic), acute and/or chronic. The PDE4inhibitors of the subject invention may also be useful in conditionswhere NSAIDs, morphine or fentanyl opiates and/or other opioidanalgesics would traditionally be administered.

In addition, compounds disclosed herein may be used in the treatment ofinsulin resistance and other metabolic disorders such as atherosclerosisthat are typically associated with an exaggerated inflammatorysignaling.

Compounds disclosed herein may also be used in the treatment ofrespiratory disease or conditions, including therapeutic methods of usein medicine for preventing and treating a respiratory disease orcondition including: asthmatic conditions including allergen-inducedasthma, exercise-induced asthma, pollution-induced asthma, cold-inducedasthma, and viral-induced-asthma; asthma-related diseases such as airwayhyperreactivity and small airway disease; chronic obstructive pulmonarydiseases including chronic bronchitis with normal airflow, chronicbronchitis with airway obstruction (chronic obstructive bronchitis),emphysema, asthmatic bronchitis, and bullous disease; and otherpulmonary diseases involving inflammation including bronchiolitis,bronchioectasis, cystic fibrosis, pigeon fancier's disease, farmer'slung, acute respiratory distress syndrome, pneumonia, pneumonitis,aspiration or inhalation injury, fat embolism in the lung, acidosisinflammation of the lung, acute pulmonary edema, acute mountainsickness, acute pulmonary hypertension, persistent pulmonaryhypertension of the newborn, perinatal aspiration syndrome, hyalinemembrane disease, acute pulmonary thromboembolism, heparin-protaminereactions, sepsis, status asthamticus, hypoxia, dyspnea, hypercapnea,hyperinflation, hypoxemia, and cough. Further, compounds disclosedherein would find use in the treatment of allergic disorders such asdelayed type hypersensitivity reaction, allergic contact dermatitis,allergic rhinitis, and chronic sinusitis.

Compounds disclosed herein may also be used in the treatment ofinflammation and related disorders. The compounds disclosed herein maybe useful as anti-inflammatory agents with the additional benefit ofhaving significantly less harmful side effects. The compounds may beuseful to treat arthritis, including but not limited to rheumatoidarthritis, spondyloarthropathies, gouty arthritis, osteoarthritis,juvenile arthritis, acute rheumatic arthritis, enteropathic arthritis,neuropathic arthritis, psoriatic arthritis, reactive arthritis (Reiter'ssyndrome), and pyogenic arthritis, and autoimmune diseases, includingsystemic lupus erythematosus, hemolytic syndromes, autoimmune hepatitis,autoimmune neuropathy, vitiligo (autoimmune thyroiditis), Hashimoto'sthyroiditis, anemias, myositis including polymyositis, alopecia greata,Goodpasture's syndrome, hypophytis, and pulmonary fibrosis.

Compounds disclosed herein may also be used in the treatment ofosteoporosis and other related bone disorders.

Compounds disclosed herein may also be used in the treatment ofgastrointestinal conditions such as reflux esophagitis, diarrhea,inflammatory bowel disease, Crohn's disease, gastritis, irritable bowelsyndrome, Graves' disease (hyperthyroidism), necrotizing enterocolitis,and ulcerative colitis. The compounds may also be used in the treatmentof pulmonary inflammation, such as that associated with viral infectionsand cystic fibrosis.

In addition, compounds of invention may also be useful in organtransplant patients either alone or in combination with conventionalimmunomodulators. Examples of conditions to be treated in said patientsinclude graft vs. host reaction (i.e., graft vs. host disease),allograft rejections (e.g., acute allograft rejection, and chronicallograft rejection), transplant reperfusion injury, and earlytransplantation rejection (e.g., acute allograft rejection).

Yet further, the compounds of the invention may be useful in thetreatment of pruritus and vitiligo.

Compounds disclosed herein may also be used in the treatment of tissuedamage in such diseases as vascular diseases, migraine headaches,periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,sclerodoma, rheumatic fever, type I diabetes, neuromuscular junctiondisease including myasthenia gravis, white matter disease includingmultiple sclerosis, sarcoidosis, nephritis, nephrotic syndrome,Langerhans' cell histiocytosis, glomerulonephritis, reperfusion injury,pancreatitis, interstitial cystitis, Behcet's syndrome, polymyositis,gingivitis, periodontis, hypersensitivity, swelling occurring afterinjury, ischemias including myocardial ischemia, cardiovascularischemia, and ischemia secondary to cardiac arrest, cirrhosis, septicshock, endotoxic shock, gram negative sepsis, toxic shock syndrome,stroke, ischemia reperfusion injury, multi-organ dysfunction, restenosisincluding restenosis following coronary bypass surgery, and the like.

Furthermore, the compounds disclose herein may also be useful ininhibiting PDE4 activity for the amelioration of systemic disordersincluding systemic hypotension associated with septic and/or toxichemorrhagic shock induced by a wide variety of agents; as a therapy withcytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short termimmunosuppression in transplant therapy.

Compounds disclosed herein may also be used in the treatment of cancer,such as colorectal cancer, and cancer of the breast, lung, prostate,bladder, cervix and skin. Compounds of the invention may be used in thetreatment and prevention of neoplasias including but not limited tobrain cancer, bone cancer, leukemia, lymphoma, epithelial cell-derivedneoplasia (epithelial carcinoma) such as basal cell carcinoma,adenocarcinoma, gastrointestinal cancer such as lip cancer, mouthcancer, esophageal cancer, small bowel cancer and stomach cancer, coloncancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,cervical cancer, lung cancer, breast cancer and skin cancer, such assquamous cell and basal cell cancers, prostate cancer, renal cellcarcinoma, and other known cancers that effect epithelial cellsthroughout the body. The neoplasia can be selected from gastrointestinalcancer, liver cancer, bladder cancer, pancreas cancer, ovary cancer,prostate cancer, cervical cancer, lung cancer, breast cancer and skincancer, such as squamous cell and basal cell cancers. The presentcompounds and methods may also be used to treat the fibrosis whichoccurs with radiation therapy. The present compounds and methods may beused to treat subjects having adenomatous polyps, including those withfamilial adenomatous polyposis (FAP). Additionally, the presentcompounds and methods may be used to prevent polyps from forming inpatients at risk of FAP.

Compounds disclosed herein may also be used in the treatment of oticdiseases and otic allergic disorders, including eustachian tube itching.

Compounds disclosed herein may also be used in the treatment ofophthalmic diseases.

Moreover, compounds of the subject invention may be used in thetreatment of menstrual cramps, dysmenorrhea, premature labor,endometriosis, tendonitis, bursitis, skin-related conditions such aspsoriasis, eczema, burns, sunburn, dermatitis, pancreatitis, hepatitis,lichen planus, scleritis, scleroderma, dermatomyositis, and the like.Other conditions in which the compounds of the subject invention may beused include diabetes (type I or type II), atherosclerosis, congestiveheart failure, myocarditis, atherosclerosis, cerebral ischemia,angiogenesis, pulmonary hypertension, and aortic aneurysm.

The compounds disclosed herein may also be used in co-therapies,partially or completely, in place of other conventionalanti-inflammatory therapies, such as together with steroids, NSAIDs,COX-2 selective inhibitors, 5-lipoxygenase inhibitors, LTB₄ antagonistsand LTA₄ hydrolase inhibitors. Additional co-therapies comprising thecompounds disclosed herein with biologics include:

-   -   tumor necrosis factor alpha (TNFα) blockers such as etanercept        (Enbrel), infliximab (Remicade), adalimumab (Humira),        certolizumab pegol (Cimzia), and golimumab (Simponi);    -   Interleukin 1 (IL-1) blockers such as anakinra (Kineret);    -   monoclonal antibodies against B cells such as rituximab        (Rituxan);    -   T cell costimulation blocker such as abatacept (Orencia); and    -   Interleukin 6 (IL-6) blockers such as tocilizumab (RoActemra or        Actemra, an anti-IL-6 receptor antibody).

Compounds disclosed herein may also be used to prevent tissue damagewhen therapeutically combined with antibacterial or antiviral agents. Incertain embodiments, the compounds disclosed hereinmay be combined withneuraminidase inhibitors for the treatment of a viral disease such asinfluenza.

Besides being useful for human treatment, certain compounds andformulations disclosed herein may also be useful for veterinarytreatment of companion animals, exotic animals and farm animals,including mammals, rodents, and the like. More preferred animals includehorses, dogs, and cats.

All references, patents or applications, U.S. or foreign, cited in theapplication are hereby incorporated by reference as if written herein intheir entireties. Where any inconsistencies arise, material literallydisclosed herein controls.

General Synthetic Methods for Preparing Compounds

The following schemes and general procedures can be used to practice thepresent invention.

Example R R₁ R₂ 22

Me

23

Me

24

Me

25

26

27

28

29

33

35

Cl

37

38

39

40

41

43

44

45

46

46

48

49

50

53

54

55

56

59

61

63

64

Variation on Scheme 2: Synthesis of cyclopenta[b]pyridine Analogs

EXAMPLE R1 R2 1 CH₂CN 2 CH₂(CO)OMe CH₂CO₂H 3 CH₂CN CH₂(CO)NH₂ 4OCH₂C(O)OMe OCH₂CO₂H 5 C(O)OMe CO₂H 6 CH₂C(O)OMe CH₂CH₂OH 8CH₂CH₂CH₂C(O)OMe CH₂CH₂CH₂CO₂H 9 CH₂CH₂C(O)OMe CH2CH₂CO₂H

EXAMPLE R1 R2 17 CH₂CN — 7 CH₂(CO)OMe CH₂CO₂H

Variation on Scheme 4: Synthesis of cyclopenta[b]pyrimidine Analogs

EXAMPLE R1 R2  9

10

11

12

13

14

15

16

18

19

20

21

Step 1. Ethyl 3-chlorobenzimidate hydrochloride

A 500-mL round bottomed flask was charged with 3-chlorobenzonitrile(23.3 g, 169 mmol, 1 eq.), ethanol (8.48 g, 184 mmol, 1.09 eq.), and HCl(4 N in dioxane, 169 mL, 676 mmol, 4 eq.). The resulting mixture wasstirred at room temperature for 54 hr. The volatile material was removedunder reduced pressure and the residue was treated with ether. Theresulting solid was collected by filtration and washed with ether. Theproduct was used in the next step without further purification (26.9 g,84% yield). ¹H NMR (DMSO-d₆, 500 MHz) δ 12.0 (br s, 2H), 8.25-8.20 (m,1H), 8.12-8.08 (m, 1H), 7.90-7.85 (m, 1H), 7.67 (t, J=8.0 Hz, 1H), 4.63(q, J=7.0 Hz, 2H), 1.48 (t, J=7.0 Hz, 3H).

Step 2. 3-Chlorobenzimidamide

A 1-L round bottom flask was charged with ethyl 3-chlorobenzimidatehydrochloride (26.9 g, mmol, 122 mmol, 1 eq.) and NH₃ (7N in methanol,360 mL, 2.52 mol, 20 eq.) in methanol (270 mL). The resulting mixturewas stirred at room temperature for 3 days. The volatile material wasremoved under reduced pressure and the resultant off-white solid wasused in the next step without further purification (23.9 g, 89% yield).¹H NMR (DMSO-d₆, 500 MHz) δ 9.48 (br s, 4H), 7.97-7.94 (m, 1H),7.84-7.79 (m, 2H), 7.65 (t, J=8.0 Hz, 1H).

Step 3. 2-(3-Chlorophenyl)-6-ethylpyrimidin-4(3H)-one

A 1-L round bottomed flask was charged with 3-chlorobenzimidamide (23.9g, 154 mmol, 1 eq.), ethyl 3-oxopentanoate (27.8 g, 193 mmol, 1.25 eq.),and ethanol (500 mL). To the mixture was added sodium methoxide (10.0 g,185 mmol, 1.20 eq.). The resulting mixture was stirred under reflux for20 hr. After cooling to room temperature, the mixture was evaporatedunder reduced pressure to 50 mL. The residual slurry was cautiouslytreated with 2N HCl (219 mL). Solid was collected by filtration andwashed with water followed by ether to afford2-(3-chlorophenyl)-6-ethylpyrimidin-4(3H)-one (9.3 g, 39% yield), whichwas carried forward into the next step without further purification. ¹HNMR (CD₃OD, 500 MHz) δ 8.07 (s, 1H), 7.96 (d, J=8.0 Hz, 1H), 7.62-7.58(m, 1H), 7.52 (t, J=8.0, Hz, 1H), 6.27 (s, 1H), 2.66 (q, J=7.5 Hz, 2H),1.29 (t, J=7.5 Hz, 3H).

Step 4. 4-Chloro-2-(3-chlorophenyl)-6-ethylpyrimidine

A 250-mL round bottom flask was charged with2-(3-chlorophenyl)-6-ethylpyrimidin-4(3H)-one (9.3 g, 39.8 mmol, 1 eq.).POCl₃ (50 mL, 536 mm01, 13.4 eq.) was cautiously added at 0° C. Theresulting mixture was stirred at 100° C. for 5 hr. After cooling to roomtemperature, the mixture was added slowly dropwise to cold aq. NaHCO₃.NaOH was added to keep the pH ˜7 during quenching. The mixture wasextracted with ethyl acetate. The organic extract was dried over sodiumsulfate, filtered and concentrated under reduced pressure. Purificationby silica gel chromatography using dichloromethane/ethyl acetate aseluent afforded 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (9.3 g,99% yield) as a white solid. ¹H NMR (CD₃OD, 500 MHz) δ 8.32 (s, 1H),8.28 (d, J=7.5 Hz, 1H), 7.50-7.46 (m, 1H), 7.45-7.40 (m, 1H), 7.27 (s,1H), 2.83 (q, J=7.5 Hz, 2H), 1.34 (t, J=7.5 Hz, 3H).

The following general procedures may be used in the synthesis ofcompounds disclosed herein.

General Procedure A1 (Nucleophilic Addition)

To a solution of chloropyridine.HCl or chloropyrimidine (1.0 equiv) inDMF or NMP was added the requisite aniline (1.0-1.5 equiv) and thereaction mixture was stirred with heat between 120-160° C. for 12-24 hor until the starting material was consumed (monitored by LCMSanalysis). The reaction mixture was cooled, diluted with saturatedaqueous sodium bicarbonate and/or water and extracted with ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product. In some cases, HCl in methanolwas used to form HCl salt of the desired product.

General Procedure A2 (Nucleophilic Addition)

To a solution of chloropyridine.HCl or chloropyrimidine (1.0 equiv) inDMF or NMP was added the requisite aniline (1.0-1.5 equiv) and thereaction mixture was heated with microwave irradiation between 120-160°C. for 1-4 h or until the starting material was consumed (monitored byLCMS analysis). The reaction mixture was cooled, diluted with satd. aq.sodium bicarbonate and/or water and extracted with ethyl acetate. Thecombined organic layer was dried over anhydrous sodium sulfate, filteredand the filtrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product. In some cases, HCl in methanolwas used to form HCl salt of the desired product.

General Procedure B1 (Palladium Coupling)

To a solution of chloropyridine or chloropyrimidine (1.0 equiv) indioxane was added palladium acetate (5 mol %), rac-BINAP (7.5 mol %),cesium carbonate (2.5 equiv), and the requisite aniline or amine (1-1.2equiv). Nitrogen gas was passed through the suspension for 10 min. Thereaction mixture was stirred with heat between 80-120° C. for 2-24 h oruntil the starting material was consumed (monitored by LCMS analysis).The reaction mixture was cooled, diluted with water and extracted withethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by column chromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product. In some cases, HCl in methanolwas used to form HCl salt of the desired product.

General Procedure B2 (Palladium Coupling)

To a solution of chloropyridine or chloropyrimidine (1.0 equiv) indioxane was added palladium acetate (5 mol %), rac-BINAP (7.5 mol %),cesium carbonate (2.5 equiv), and the requisite aniline or amine (1-1.2equiv). The reaction mixture was heated with microwave irradiationbetween 100-120° C. for 1-4 h or until the starting material wasconsumed (monitored by LCMS analysis). The reaction mixture was cooled,diluted with water, and extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product. In some cases, HCl in methanolwas used to form HCl salt of the desired product.

General Procedure C (Amide Formation)

To a microwave vessel was added the methyl or ethyl ester. Ammonia inmethanol (7 M, 3-10 mL) was added and the vessel was sealed with analuminum cap. The resulting mixture was stirred at 100° C. for 24-48 h.The crude reaction solution was cooled, evaporated and purified bycolumn chromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product. In some cases, HCl in methanolwas used to form HCl salt of the desired product.

General Procedure D (Saponification)

To a solution of methyl or ethyl ester (1.0 equiv) in dioxane and water(2:1) was added lithium hydroxide (5 equiv). The suspension was stirredfor 4-24 h or until the starting material was consumed (monitored byLCMS analysis). The reaction was diluted with water, acidified with HCl(2 M), and extracted with ethyl acetate. The combined organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate or methanol/dichloromethane) or preparative HPLC(water/acetonitrile with 0.05% TFA) to afford the desired product.

General Procedure E1 (Reduction—DIBAL)

To a solution of methyl or ethyl ester (1.0 equiv) in DCM at 0° C. wasadded DIBAL (3 equiv, 1.0 M in THF). The mixture was stirred for 2 h andwarmed to rt for 30 min or until the starting material was consumed(monitored by LCMS analysis). The reaction was quenched with methanol,HCl (2 M), and water and then extracted with DCM. The combined organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product.

General Procedure E2 (Reduction—BH₃)

To a solution of methyl or ethyl ester or carboxylic acid (1.0 equiv) inTHF at 0° C. was added BH₃.DMS (2 equiv). The mixture was warmed to rand stirred for 4 h or until the starting material was consumed(monitored by LCMS analysis). The reaction was quenched with HCl (0.5M), diluted with satd. aq. sodium bicarbonate, and extracted with ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product. In some cases, HCl in methanolwas used to form HCl salt of the desired product.

General Procedure F (Suzuki Coupling)

To a solution of dichloropyridine (1.0 equiv) in toluene/ethanol (2:1)was added boronic acid or ester (1.1 equiv), cesium carbonate (3 equiv)and tetrakis(triphenylphosphine)palladium (5 mol %). Nitrogen gas waspassed through the suspension for 10 min. The reaction mixture wasstirred with heat at 90° C. for 2-6 h or until the starting material wasconsumed (monitored by LCMS analysis). The reaction mixture was cooled,diluted with water, and extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the desiredproduct.

General Procedure G (Suzuki Coupling)

To a solution of chloropyridine or chloropyrimidine (1.0 equiv) indioxane was added boronic ester (1.0-1.2 equiv), Pd(dppf)Cl₂ (10 mol %),and sodium carbonate (3 equiv). The mixture was degassed with a seriesof vacuum/argon exchanges. The reaction mixture was stirred with heatbetween 80-90° C. for 1-4 h or until the starting material was consumed(monitored by LCMS analysis). The reaction mixture was cooled, dilutedwith water, and extracted with ethyl acetate. The combined organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate or methanol/dichloromethane) or preparative HPLC(water/acetonitrile with 0.05% TFA) to afford the desired product. Insome cases, HCl in methanol was used to form HCl salt of the desiredproduct.

General Procedure H

To a solution of pyrimidinyl trifluoromethanesulfonate (1.0 equiv) inDMF was added the requisite aniline (1.0-1.5 equiv) and the reactionmixture was stirred with heat between 70-85° C. for 1-16 h or until thestarting material was consumed (monitored by LCMS analysis). Thereaction mixture was cooled, diluted with ethyl acetate and washed withwater. The combined organic layer was dried over anhydrous sodiumsulfate, filtered and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate ormethanol/dichloromethane) or preparative HPLC (water/acetonitrile with0.05% TFA) to afford the desired product.

The invention is further illustrated by the following examples. In theExamples below, abbreviations are used which have meanings known in theart. For example: rt means room temperature; aq means aqueous; eq meansequivalent; TLC means thin layer chromatography; Ar means argon; atmmeans atmosphere, a measurement; m.p. means melting point; and DCM meansdichloromethane.

EXAMPLE 12-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile

Step 1. 4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridineHCl salt

An 18-mL vial was charged with2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine HCl salt (225 mg, 1mmol, 1 eq.), (3-chlorophenyl)boronic acid (165 mg, 1.06 mmol, 1.06eq.), tetrakis(triphenylphosphine)palladium(0) (84 mg, 0.07 mmol, 0.07eq.), and K₂CO₃ (500 mg, 3.6 mmol, 3.6 eq.). Toluene (6 ml), EtOH (2 ml)and water (2.5 ml) were added. The resulting mixture was stirred underAr at 90° C. for 4 hr. until the starting chloride was consumed. Aftercooling to room temperature, the aqueous layer was separated and theorganic layer was concentrated on a rotary evaporator. The residue waspurified by chromatography on silica gel using hexane/dichloromethane(9:1 then 8:1) as eluent to afford4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine, whichwas converted into its corresponding HCl salt by treating with 4N HCl indioxane (228 mg, 76% yield).

Step 2.2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile

An 18-mL test tube was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HClsalt (30 mg, 0.1 mmol, 1 eq.) and 2-(4-aminophenyl)acetonitrile (30 mg,0.23 mmol, 2.3 eq.). The resulting mixture was heated at 150° C. underAr for 1 hr. After cooling to room temperature, the mixture waspartitioned between NaHCO₃ aq. (10 ml) and dichloromethane (10 ml). Theorganic layer was collected and concentrated on a rotary evaporator. Theresidue was purified by chromatography on silica gel usingdichloromethane followed by ethyl acetate as eluent to give2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile(16 mg, 44% yield). MW=359.85. ¹H NMR (CDCl₃, 360 MHz) δ 7.84 (s, 1H),7.68 (m, 1H), 7.32 (m, 4H), 7.21 (m, 2H), 7.15 (s, 1H), 5.82 (brs, 1H),3.75 (s, 2H), 3.09 (t, J=7.50 Hz, 2H), 2.83 (t, J=7.20 Hz, 2H), 2.21 (m,2H).

EXAMPLE 22-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]aceticacid

Step 1. Methyl 2-(4-aminophenyl)acetate

To a solution of 2-(4-aminophenyl)acetic acid (170 mg, 1.1 mmol) in amixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mLvial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N inhexane) at 0° C. After the addition was complete, the resulting mixturewas stirred at room temperature for 1 hr. The volatile material wasremoved under reduced pressure and the residue was purified bychromatography on silica gel using hexane/dichloromethane (2:1) followedby dichloromethane as eluent to give methyl 2-(4-aminophenyl)acetate asan yellowish oil (97 mg, 53% yield).

Step 2. Methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate

An 18-mL test tube was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HClsalt (30 mg, 0.1 mmol, 1 eq. Synthesis of this compound was described instep 1 of EXAMPLE 1) and methyl 2-(4-aminophenyl)acetate (33 mg, 0.2mmol, 2 eq.). The resulting mixture was heated at 150° C. under Ar for 1hr. After cooling to room temperature, the mixture was partitionedbetween NaHCO₃ aq. (10 ml) and dichloromethane (10 ml). The organiclayer was collected and concentrated on a rotary evaporator. The residuewas purified by chromatography on silica gel using dichloromethanefollowed by 1-3% of MeOH in dichloromethane as eluent to give methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate(31 mg, 77% yield).

Step3.2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]aceticacid

An 18-mL vial was charged with methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate(31 mg, 0.77 mmol, 1 eq.) and lithium hydroxide monohydrate (48 mg, 1.14mmol, 1.48 eq.). To this was added THF (1 ml) and water (0.5 ml). Theresulting mixture was stirred at room temperature overnight. Then 2N HClaq. (0.6 ml) was added. The volatile materials were removed underreduced pressure to give a residue, which was purified by chromatographyon silica gel using 2-5% of MeOH in dichloromethane as eluent to give2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]aceticacid (26 mg, HCl salt, 81% yield). MW=378.85. ¹H NMR (DMSO-D₆, 360 MHz)δ 14.23 (brs, 1H), 12.39 (brs, 1H), 9.84 (brs, 1H), 7.91 (s, 1H), 7.70(d, J=7.70 Hz, 1H), 7.63 (d, J=8.40, 1H), 7.57 (dd, J=7.70, 8.40 Hz,1H), 7.36 (brs, 4H), 7.02 (s, 1H), 3.60 (s, 2H), 3.11 (t, J=7.90 Hz,2H), 2.90 (t, J=7.40 Hz, 2H), 2.20 (m, 2H).

EXAMPLE 32-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetamide

An 18 mL-vial was charged with2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetonitrile(12 mg, 0.033 mmol, synthesis of this compound was described in EXAMPLE1). Concentrated H₂SO₄ (0.5 ml) was added at 0° C. The mixture wasstanding at room temperature for 6 hr. And then the mixture was addedvery slowly to NaHCO₃ aq. at 0° C. The precipitate was collected andwashed with water, dried. The product thus obtained was treated with 4NHCl in dioxane and the volatile material was removed under reducedpressure to give the desired product2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetamideas HCl salt (2.6 mg, 19% yield). MW=377.87. ¹H NMR (CDCl₃, 360 MHz) δ7.83 (s, 1H), 7.69 (m, 1H), 7.18-7.30 (m, 7H), 5.77 (brs, 1H), 5.44(brs, 2H), 3.58 (s, 2H), 3.08 (t, J=7.70 Hz, 2H), 2.83 (t, J=7.10 Hz,2H), 2.21 (m, 2H).

EXAMPLE 42-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]aceticacid

Step 1. Methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetate

An 18-mL vial was charged with methyl 2-(4-aminophenoxy)acetate (24 mg,0.13 mmol, 2 eq.) and4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HClsalt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture wasdissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). Afterthe volatile material was removed under reduced pressure, the residuewas heated at 150° C. under argon for 1 hr. After cooling to roomtemperature, the reaction mixture was partitioned between NaHCO₃ aq. (10ml) and ethyl acetate (10 ml). The organics was separated and dried overMgSO4. The solvent was removed under reduced pressure to give a residue,which was purified by chromatography on silica gel using dichloromethanefollowed by 0.1-0.3% methanol in dichloromethane as eluent to give thedesired product methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetateas white solid (11.8 mg, 44% yield).

Step2.2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]aceticacid HCl salt

An 18-mL vial was charged with methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]acetate(11.8 mg, 0.029 mmol, 1 eq.) and LiOH/H₂O (42 mg, 1 mmol, 34 eq.). THF(1 ml) and H₂O (0.5 ml) was added to the vial. The resulting mixture wasstirred at room temperature overnight. 2 N HCl aq. (0.5 ml) was addedand the volatile material was removed under reduced pressure. Theresidue was purified by chromatography on silica gel usingdichloromethane followed by 10% of methanol in dichloromethane as eluentto give2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]aceticacid, which was treated with 4N HCl in dioxane (2 ml). After thevolatile material was removed under reduced pressure,2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenoxy]aceticacid HCl salt was obtained (8 mg, 65% yield). MW=431.31. ¹H NMR(DMSO-D₆, 360 MHz) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.47 (m, 2H), 7.23 (m,2H), 6.94 (m, 3H), 4.67 (s, 2H), 2.95 (m, 2H), 2.82 (m, 2H), 2.09 (m,2H).

EXAMPLE 54-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoicacid

Step 1. Methyl4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate

An 18-mL vial was charged with methyl 4-aminobenzoate (20 mg, 0.13 mmol,2 eq.) and4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HClsalt (20 mg, 0.066 mmol, 1 eq. See step 1 of EXAMPLE 1). The mixture wasdissolved in a mixture of MeOH (1 ml) and dichloromethane (2 ml). Afterthe volatile material was removed under reduced pressure, the residuewas heated at 150° C. under argon for 1 hr. After cooling to roomtemperature, the reaction mixture was partitioned between NaHCO₃ aq. (10ml) and ethyl acetate (10 ml). The organics was separated and dried overMgSO4. The solvent was removed under reduced pressure to give a residue,which was purified by chromatography on silica gel using dichloromethanefollowed by ethyl acetate as eluent to give the desired product methyl4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate(21.6 mg, 86% yield).

Step 2.4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoicacid

An 18-mL vial was charged with methyl4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoate(20 mg, 0.053 mmol, 1 eq.) and LiOH/H₂O (47.4 mg, 1.13 mmol, 21 eq.).THF (1 ml), H₂O (0.3 ml) and MeOH (0.2 ml) was added to the vial. Theresulting mixture was stirred at room temperature overnight. 2 N HCl aq.(0.5 ml) was added and the volatile material was removed under reducedpressure. The residue was purified by chromatography on silica gel using5% of methanol in dichloromethane as eluent to give4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]benzoicacid (4.8 mg, 25% yield). MW=364.82. ¹H NMR (DMSO-D₆, 360 MHz) δ 8.65(s, 1H), 7.96 (s, 1H), 7.86 (m, 3H), 7.42 (m, 3H), 7.25 (d, J=8.31 Hz,2H), 2.92 (t, J=7.86, 2H), 2.82 (t, J=6.93, 2H), 2.06 (m, 2H).

EXAMPLE 62-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]ethanol

Step 1. Methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate

See step 2 in EXAMPLE 2.

Step2.2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]ethanol

An 18-mL vial was charged with methyl2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]acetate(20.7 mg, 0.053 mmol) and THF (2 ml). To the mixture was added LiAlH₄(20 mg, 0.53 mmol, 10 eq.) portion-wise at 0 C. After the addition wascomplete, the resulting mixture was stirred under Ar at rt overnight. 2NHCl aq. (2 ml) was added followed by saturated NaHCO₃ aq. The mixturewas extracted with ethyl acetate (3×5 ml). The organic layer wascombined and concentrated on a rotary evaporator. The residue waspurified by chromatography on silica gel using dichloromethane followedby ethyl acetate as eluent to afford the desired product (15 mg), ofwhich ¹H NMR indicates it contains impurities. The product thus obtainedwas re-purified by chromatography on silica gel using DCM followed byDCM/EA with a ratio of 9:1 to 2:1 in favor of DCM as eluent to give2-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]ethanol(3.5 mg, 18% yield). MW=264.87. ¹H NMR (CDCl₃, 360 MHz) δ 7.84 (m, 2H),7.41 (m, 3H), 7.21 (m, 3H), 7.16 (s, 1H), 5.95 (brs, 1H), 3.90 (m, 2H),3.18 (m, 2H), 2.87 (m, 4H), 2.24 (m, 2H).

EXAMPLE 72-[4-[[6-(3-Chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]aceticacid

Step 1. Ethyl (Z)-3-amino-2-ethyl-but-2-enoate

A 100-mL round bottom flask was charged with ethyl2-ethyl-3-oxo-butanoate (5 g, 90% purity, 28 mmol), ammonium acetate (22g, 280 mmol, 10 eq.), ammonia (2N in EtOH, 14 ml, 1 eq.), anhydroussodium sulfate (8 g, 56 mmol, 2 eq.) and MeOH (30 ml). The resultingmixture was stirred at room temperature overnight. The volatile materialwas removed under reduced pressure and the residue was treated withdichloromethane (40 ml). Insoluble material was removed by filtrationand washed with dichloromethane (2×20 ml). The organics was washed withaqueous sodium bicarbonate, dried over Na₂SO₄. Removal of solvent gaveethyl (Z)-3-amino-2-ethyl-but-2-enoate (4.1 g, 82% yield) as a whitesolid.

Step 2. Ethyl(Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate

A 100-mL round bottom flask was charged with ethyl(Z)-3-amino-2-ethyl-but-2-enoate (880 mg, 5.6 mmol, 1 eq.),diisopropylethylamine (750 mg, 5.8 mmol, 1.04 eq.) and THF (10 ml). Tothe mixture was added ethyl 3-chloro-3-oxo-propanoate (840 mg, 5.6 mmol,1 eq.) drop-wise by a syringe at 0° C. After the addition was complete,the resulting mixture was stirred at room temperature overnight and thenadded to aqueous sodium bicarbonate solution. The mixture was extractedwith ethyl acetate (3×15 ml). The combined organic layer was dried overanhydrous Na₂SO₄. Removal of solvent gave the crude product ethyl(Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate as yellowoil (1.3 g, 86% yield).

Step 3. Ethyl 5-ethyl-4-hydroxy-6-methyl-2-oxo-1H-pyridine-3-carboxylate

A 50-mL round bottom flask was charged with ethyl(Z)-3-[(3-ethoxy-3-oxo-propanoyl)amino]-2-ethyl-but-2-enoate (540 mg, 2mmol, 1 eq.), sodium methoxide (750 mg, 6.8 mmol, 3.4 eq. 25 wt. % inMeOH) and EtOH (10 ml). The mixture was stirred under reflux for 1 hr.After cooling to room temperature, the mixture was acidified by additionof 2N HCl aq. (5 ml) and extracted with ethyl acetate (3×10 ml). Thecombined organic layers were dried over anhydrous sodium sulfate andconcentrated on a rotary evaporator to afford crude ethyl5-ethyl-4-hydroxy-6-methyl-2-oxo-1H-pyridine-3-carboxylate (205 mg, 46%yield) as yellow solid.

Step 4. 5-Ethyl-4-hydroxy-6-methyl-1H-pyridin-2-one

A 50-mL round bottom flask was charged with ethyl5-ethyl-4-hydroxy-6-methyl-2-oxo-1H-pyridine-3-carboxylate (117 mg, 0.52mmol) and 1N HCl (10 ml). The mixture was stirred under refluxovernight. After cooling to room temperature, the mixture wasneutralized by addition of aqueous NaHCO₃ to pH=7. The precipitate wascollected by filtration and washed with water. After dried,5-ethyl-4-hydroxy-6-methyl-1H-pyridin-2-one was obtained (43 mg, 54%yield).

Step 5. 4,6-Dichloro-3-ethyl-2-methyl-pyridine

A 18-mL vial was charged with5-ethyl-4-hydroxy-6-methyl-1H-pyridin-2-one (200 mg, 1.3 mmol). POCl₃ (1ml) was added. The resulting mixture was stirred at 90 C overnight.After cooling to room temperature, the volatile material was removedunder reduced pressure and the residue was partitioned between ethylacetate and aqueous sodium bicarbonate solution. The organic layer wasseparated and passed through a plug of silica gel. Removal of solventunder reduced pressure gave 4, 6-dichloro-3-ethyl-2-methyl-pyridine (100mg, 40% yield).

Step 6. 4-Chloro-6-(3-chlorophenyl)-3-ethyl-2-methyl-pyridine

A 50-mL round bottomed flask was charged with2,4-dichloro-5-ethyl-6-methyl-1,2-dihydropyridine (94 mg, 0.49 mmol, 1eq.), (3-chlorophenyl)boronic acid (77 mg, 0.49 mmol, 1 eq.),tetrakis(triphenylphosphine)palladium(0) (50 mg, 0.09 mmol, 0.09 eq.),and K₂CO₃ (200 mg, 1.45 mmol, 3 eq.). Toluene (4 ml), EtOH (1.6 ml) andwater (1.6 ml) were added. The resulting mixture was stirred under Ar at90° C. for 3 hr. until the starting chloride was consumed. After coolingto room temperature, the aqueous layer was separated and the organiclayer was concentrated on a rotary evaporator. The residue was purifiedby chromatography on silica gel using hexane/dichloromethane (49:1, then9:1 and 8:1) as eluent to afford4-chloro-6-(3-chlorophenyl)-3-ethyl-2-methyl-pyridine, which wasconverted into its corresponding HCl salt by treating with 4N HCl indioxane (120 mg, 81% yield).

Step 7. Methyl2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate

An 18-mL test tube was charged with4-Chloro-6-(3-chlorophenyl)-3-ethyl-2-methyl-pyridine HCl salt (15 mg,0.05 mmol, 1 eq.) and methyl 2-(4-aminophenyl)acetate (20 mg, 0.12 mmol,2.4 eq.). The resulting mixture was heated at 150° C. under Ar for 1 hr.After cooling to room temperature, the mixture was partitioned betweenNaHCO₃ aq. (10 ml) and dichloromethane (10 ml). The organic layer wascollected and concentrated on a rotary evaporator. The residue waspurified by chromatography on silica gel using dichloromethane/ethylacetate (9:1 then 3:1) as eluent to give methyl2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate(8 mg, 41% yield).

Step 8.2-[4-[[6-(3-Chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]aceticacid

An 18-mL vial was charged with methyl2-[4-[[6-(3-chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]acetate(8 mg, 0.02 mmol, 1 eq.) and lithium hydroxide monohydrate (13 mg, 0.31mmol, 15 eq.). To this was added THF (1 ml) and water (0.4 ml). Theresulting mixture was stirred at room temperature overnight. Then 2N HClaq. (0.12 ml) was added. The volatile materials were removed underreduced pressure to give a residue, which was purified by chromatographyon silica gel using 2-4% of MeOH in dichloromethane as eluent to give2-[4-[[6-(3-Chlorophenyl)-3-ethyl-2-methyl-4-pyridyl]amino]phenyl]aceticacid (7 mg, 91% yield). MW=380.87. ¹H NMR (Methanol-D₄, 360 MHz) δ 7.69(s, 1H), 7.48-7.58 (m, 3H), 7.44 (d, J=8.2 Hz, 2H), 7.33 (d, J=8.2 Hz,2H), 6.89 (s, 1H), 3.67 (s, 2H), 2.85 (q, J=7.5 Hz, 2H), 2.66 (s, 3H),1.24 (t, J=7.5 Hz, 3H).

EXAMPLE 84-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoicacid

Step 1. Methyl 4-(4-aminophenyl)butanoate

To a solution of 4-(4-aminophenyl)butanoic acid (180 mg, 1 mmol) in amixture of THF (4 ml), MeOH (1 ml) and dichloromethane (1 ml) in a 20-mLvial was added dropwise (trimethylsilyl)diazo-methane (1 ml, 2N inhexane) at 0° C. After the addition was complete, the resulting mixturewas stirred at room temperature for 1 hr. The volatile material wasremoved under reduced pressure and the residue was purified bychromatography on silica gel using hexane/dichloromethane (2:1) followedby dichloromethane as eluent to give methyl 4-(4-aminophenyl)butanoateas an yellowish oil (55 mg, 28% yield).

Step 2. Methyl4-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoate

An 18-mL test tube was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine HClsalt (10 mg, 0.033 mmol, 1 eq. Synthesis of this compound was describedin step 1 of EXAMPLE 1) and methyl 4-(4-aminophenyl)butanoate (17 mg,0.088 mmol, 2.7 eq.). The resulting mixture was heated at 150° C. underAr for 1 hr. After cooling to room temperature, the mixture waspartitioned between NaHCO₃ aq. (10 ml) and dichloromethane (10 ml). Theorganic layer was collected and concentrated on a rotary evaporator. Theresidue was purified by chromatography on silica gel usingdichloromethane followed by 5% of ethyl acetate in dichloromethane aseluent to give methyl4-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoate(11 mg, 79% yield).

Step 34-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoicacid

An 18-mL vial was charged with methyl4-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl]amino]phenyl]butanoate(10 mg, 0.024 mmol, 1 eq.) and lithium hydroxide monohydrate (45 mg,1.07 mmol, 44 eq.). To this was added THF (1 ml) and water (0.5 ml). Theresulting mixture was stirred at room temperature overnight. Then 1N HClaq. (1 ml) was added. The volatile materials were removed under reducedpressure to give a residue, which was purified by chromatography onsilica gel using 2˜4% of MeOH in dichloromethane as eluent to give thetitle compound (7.8 mg, 80% yield). MW=406.90. ¹H NMR (DMSO-D₆, 400 MHz)δ 8.11 (s, 1H), 7.91 (s, 1H), 7.74 (m, 1H), 7.42 (m, 2H), 7.20 (m, 5H),2.93 (m, 2H), 2.82 (m, 2H), 2.58 (m, 2H), 2.26 (m, 2H), 2.10 (m, 2H),1.79 (m, 2H).

EXAMPLE 92-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid

Step 1, 5-Chlorothiophene-2-carboxamidine HCl Salt

An 18-mL vial was charged with 5-chlorothiophene-2-carbonitrile (1 g, 7mmol, 1 eq.), methanol (5 ml), Sodium methoxide (25 w % in methanol, 151mg, 0.7 mmol, 0.1 eq.) was added. The mixture was stirred at rt for 3hr. and then ammonium chloride (470 mg, 8.8 mmol, 1.25 eq.) was added.The resulting mixture was stirred at rt for 48 hr. The volatile materialwas removed under reduced pressure and the residue was treated withether. The solid was collected by filtration and washed with ether,dried. The crude product (1.42 g) thus obtained contains inorganic saltand was forwarded to the next step without any further purification.

Step 2,2-(5-Chloro-2-thienyl)-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one

A 50-mL round bottomed flask was charged with5-chlorothiophene-2-carboxamidine HCl salt (400 mg, ˜2 mmol, 1 eq.),ethyl 2-oxocyclopentanecarboxylate (320 mg, 2 mmol, 1 eq.), and ethanol(10 ml). To the mixture was added sodium methoxide (25 w % in methanol,540 mg, 2.5 mmol, 1.25 eq.). The resulting mixture was stirred underreflux for 20 hr. After cooling to room temperature, the mixture wasevaporated under reduced pressure to dryness and the residue was treatedwith 1N HCl (6 ml). Solid was collected by filtration and washed waterfollowed by ether. The product thus obtained was forwarded to the nextstep without any further purification (360 mg, 71% yield).

Step 3,4-Chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

An 18-mL vial was charged with2-(5-chloro-2-thienyl)-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one(180 mg, 0.71 mmol). POCl₃ (1 ml) was added. The resulting mixture wasstirred at 90° C. for 4 hr. After cooling to room temperature, themixture was added dropwise slowly to cold NaHCO₃ aq. Dichloromethane wasadded. The organic layer was separated and passed through a plug ofsilica gel, using dichloromethane as eluent to give4-chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(178 mg, 92% yield).

Step 4,2-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid

An 18-mL vial was charged with4-chloro-2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(30 mg, 0.11 mmol, 1.1 eq.), 2-(4-aminophenyl)acetic acid (15 mg, 0.1mmol, 1 eq.), and AcOH (1 ml). To the mixture was added HCl (4 N indioxane, 5 drops) The resulting mixture was stirred at 100° C. for 2 hr.After cooling to rt, the reaction mixture was diluted with addition ofwater. The precipitate was collected by filtration and washed with waterfollowed by dichloromethane, The product thus obtained (30 mg, 78%yield) was further treated with ethyl acetate to afford2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid (7.2 mg). MW=385.87. ¹H NMR (DMSO-D₆, 360 MHz) δ 9.22 (brs, 1H),7.76 (d, J=3.9 Hz, 1H), 7.70 (d, J=8.2 Hz, 2H), 7.26 (d, J=8.2 Hz, 2H),7.21 (d, J=3.9 Hz, 1H), 3.55 (s, 2H), 2.87 (m, 4H), 2.09 (m, 2H).

EXAMPLE 102-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid

Step 1, Ethyl 3-chlorobenzenecarboximidate hydrochloride

An 100-mL round bottomed flask was charged with 3-chlorobenzonitrile(2.75 g, 20 mmol, 1 eq.), ethanol (1 g, 22 mmol, 1.1 eq.), HCl (4 N indioxane, 20 ml, 80 mmol, 4 eq.). The resulting mixture was stirred at rtfor 48 hr. The volatile material was removed under reduced pressure andthe residue was treated with ether. Solid was collected by filtrationand washed with ether. The product thus obtained was forwarded to thenext step without any further purification (2.87 g, 65% yield).

Step 2, 3-Chlorobenzamidine hydrochloride

A 18-mL vial was charged with ethyl 3-chlorobenzenecarboximidatehydrochloride (450 mg, 2 mmol, 1 eq.) and NH₃ (2N in ethanol, 12 ml, 24mmol, 12 eq.). The resulting mixture was stirred at rt overnight. Thevolatile material was removed under reduced pressure and the productthus obtained was forwarded to the next step without any furtherpurification.

Step 3,2-(3-Chlorophenyl)-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one

2-(3-Chlorophenyl)-3,5,6,7-tetrahydrocyclopenta[d]pyrimidin-4-one wasprepared in a similar manner to that described in Step 2 of EXAMPLE 9 in45% yield on 2 mmol scale reaction (276 mg).

Step4,4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine wasprepared in a similar manner to that described in Step 3 of EXAMPLE 9 in98% yield on 0.57 mmol scale reaction (147 mg).

Step5,2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid

2-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid was prepared in a similar manner to that described in Step 4 ofEXAMPLE 9 in 38% yield on 0.1 mmol scale reaction (15 mg). MW=379.84. ¹HNMR (DMSO-D₆,360 MHz) δ 9.27 (brs, 1H), 8.24 (s, 1H), 8.19 (d, J=7.3 Hz,1H), 7.70 (d, J=8.3 Hz, 2H), 7.56 (m, 2H), 7.27 (d, J=8.3 Hz, 2H), 3.56(s, 2H), 2.95 (t, J=8.2 Hz, 2H), 2.89 (t, J=7.0 Hz, 2H), 2.12 (m, 2H).

EXAMPLE 112-Acetamido-2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid

2-Acetamido-2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid was prepared in a similar manner to that described in Step 4 ofEXAMPLE 9 using 2-acetamido-2-(4-aminophenyl)acetic acid instead of2-(4-aminophenyl)acetic acid as reactant in 99% yield on 0.058 mmolscale reaction (24.8 mg). MW=442.92. ¹H NMR (Methanol-D₄, 360 MHz) δ7.81 (d, J=8.6 Hz, 2H), 7.68 (d, J=4.0 Hz, 1H), 7.41 (d, J=8.6 Hz, 2H),7.01 (d, J=4.0 Hz, 1H), 5.42 (s, 1H), 2.94 (t, J=7.7 Hz, 2H), 2.88 (t,J=7.4 Hz, 2H), 2.18 (m, 2H), 2.01 (s, 3H).

EXAMPLE 122-Amino-2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid hydrochloride

An 18-mL vial was charged with2-acetamido-2-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]aceticacid (11 mg, 0.025 mmol) and 1N HCl aq. (1 ml). The mixture was stirredat 100° C. for 24 hr. The volatile material was removed under reducedpressure to dryness, generating the title compound as HCl salt (5.2 mg,48% yield). MW=437.34. ¹H NMR (Methanol-D₄,360 MHz) δ 7.97 (d, J=4.2 Hz,1H), 7.84 (d, J=8.6 Hz, 2H), 7.62 (d, J=8.6 Hz, 2H), 7.2 (d, J=4.0 Hz,1H), 5.17 (s, 1H), 3.17 (t, J=7.6 Hz, 2H), 3.01 (t, J=7.4 Hz, 2H), 2.35(m, 2H).

EXAMPLE 134-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]butanoicacid

The title compound was prepared in a similar manner to that described inStep 4 of EXAMPLE 9 using 4-(4-aminophenyl)butanoic acid instead of2-(4-aminophenyl)acetic acid as reactant in 42% yield on 0.033 mmolscale reaction (10 mg). MW=413.92. ¹H NMR (DMSO-D₆, 360 MHz) δ 8.87 (s,1H), 7.68 (d, J=7.8 Hz, 2H), 7.63 (brs, 1H), 7.16 (m, 3H), 2.83 (m, 4H),2.56 (m, 2H), 2.20 (t, J=7.4 Hz, 2H), 2.06 (m, 2H), 1.79 (m, 2H).

EXAMPLE 144-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]butanoicacid

The title compound was prepared in a similar manner to that described inStep 4 of EXAMPLE 9 using 4-(4-aminophenyl)butanoic acid instead of2-(4-aminophenyl)acetic acid as reactant in 24% yield on 0.033 mmolscale reaction (5.6 mg). MW=407.89. ¹H NMR (DMSO-D₆, 360 MHz) δ 8.80 (s,1H), 8.25 (m, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.51 (m, 2H), 7.17 (d, J=8.4Hz, 2H), 2.86 (m 4H), 2.56 (m, 2H), 2.22 (m, 2H), 2.08 (m, 2H), 1.79 (m,2H).

EXAMPLE 153-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]propanoicacid

The title compound was prepared in a similar manner to that described inStep 4 of EXAMPLE 9 using 3-(4-aminophenyl)propanoic acid instead of2-(4-aminophenyl)acetic acid as reactant in 41% yield on 0.036 mmolscale reaction (6 mg). MW=399.89. ¹H NMR (DMSO-D₆, 400 MHz) δ 8.80 (s,1H), 7.71 (d, J=8.4 Hz, 2H), 7.62 (d, J=4.0 Hz, 1H), 7.22 (d, J=8.4 Hz,2H), 7.16 (d, J=4.0 Hz, 1H), 2.83 (m, 6H), 2.55 (t, J=8.0 Hz, 2H), 2.07(m, 2H).

EXAMPLE 163-[4-[[2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]propanoicacid

The title compound was prepared in a similar manner to that described inStep 4 of EXAMPLE 9 using 3-(4-aminophenyl)propanoic acid instead of2-(4-aminophenyl)acetic acid as reactant in 70% yield on 0.036 mmolscale reaction (10 mg). MW=393.87. ¹H NMR (DMSO-D₆, 400 MHz) δ 8.82 (s,1H), 8.25 (m, 2H), 7.71 (d, J=8.4 Hz, 2H), 7.53 (m, 2H), 7.23 (d, J=8.4Hz, 2H), 2.88 (m, 6H), 2.52 (m, 2H), 2.10 (m, 2H).

EXAMPLE 172-(4-(6-(3-chlorophenyl)-3-ethyl-2-methylpyridin-4-ylamino)phenyl)acetonitrile

The title compound was prepared in a similar manner to those describedin step 7 of EXAMPLE 7 using 2-(4-aminophenyl)acetonitrile instead ofmethyl 2-(4-aminophenyl)acetate as reactant in 14% yield on 0.05 mmolscale reaction (2.7 mg). MW=361.87. 1H NMR (Methanol-D₄,360 MHz) δ 7.70(s, 1H), 7.54 (m, 1H), 7.36 (m, 4H), 7.23 (d, J=8.4 Hz, 2H), 7.11 (s,1H), 3.88 (s, 2H), 2.76 (q, J=7.5 Hz, 2H), 2.54 (s, 3H), 1.20 (t, J=7.5Hz, 3H).

EXAMPLE 182-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetonitrile

The title compound was prepared in a similar manner to that described inStep 4 of EXAMPLE 9 using 2-(4-aminophenyl)acetonitrile instead of2-(4-aminophenyl)acetic acid as reactant in 57% yield on 0.1 mmol scalereaction (21 mg). MW=366.87. ¹H NMR (CDCl₃, 360 MHz) δ 7.70 (d, J=8.5Hz, 2H), 7.67 (d, J=3.9 Hz, 1H), 7.34 (d, J=8.5 Hz, 2H), 6.91 (d, J=3.9Hz, 1H), 6.27 (brs, 1H), 3.75 (s, 2H), 2.98 (t, J=7.7 Hz, 2H), 2.79 (t,J=7.3 Hz, 2H), 2.18 (m, 2H).

EXAMPLE 192-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetonitrile

The title compound was prepared in a similar manner to that described inStep 4 of EXAMPLE 9 using 2-(4-aminophenyl)acetonitrile instead of2-(4-aminophenyl)acetic acid as reactant in 51% yield on 0.1 mmol scalereaction (18 mg). MW=360.84. ¹H NMR (CDCl₃, 360 MHz) δ 8.37 (s, 1H),8.25 (m, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.36 (m, 4H), 6.31 (s, 1H), 3.76(s, 2H), 3.04 (t, J=7.6 Hz, 2H), 2.83 (t, J=7.1 Hz, 2H), 2.21 (m, 2H).

EXAMPLE 202-[4-[[2-(5-chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetamide

The title compound was prepared in a similar manner to that described inEXAMPLE 3 in 69% yield on 0.049 mmol scale reaction (13 mg). MW=384.88.¹H NMR (Methanol-D₄, 360 MHz) δ 7.72 (d, J=8.6 Hz, 2H), 7.65 (d, J=4.0Hz, 1H), 7.29 (d, J=8.6 Hz, 2H), 6.98 (d, J=4.0 Hz, 1H), 3.50 (s, 2H),2.89 (m, 4H), 2.16 (m, 2H).

EXAMPLE 212-[4-[[2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetamide

The title compound was prepared in a similar manner to that described inEXAMPLE 3 in 90% yield on 0.038 mmol scale reaction (13 mg). MW=378.85.¹H NMR (Methanol-D₄, 360 MHz) δ 8.26 (s, 1H), 8.18 (m, 1H), 7.73 (d,J=8.5 Hz, 2H), 7.41 (m, 2H), 7.30 (d, J=8.5 Hz, 2H), 3.50 (s, 2H), 2.95(t, J=7.8 Hz, 2H), 2.88 (t, J=7.4 Hz, 2H), 2.17 (m, 2H).

EXAMPLE 22 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine

Step 1. 5-Chloro-N-cyanothiophene-2-carboximidamide

To a solution of 5-chlorothiophene-2-carbonitrile 1 in MeOH was addedNaOCH₃. The reaction mixture was stirred at room temperature for 4 h andthen NH₂CN was added. The reaction was allowed stir for overnight underN₂. The mixture was then poured into NH₄Cl(aq) and the precipitatecollected and washed with water. The dried sample was confirmed asdesired product 5-chloro-N-cyanothiophene-2-carboximidamide 2.

Step 2. 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine

To a solution of reactant 3 in CH₃CN was added reactant 2 and POCl₃. Themixture was stirred at 70° C. overnight under N₂. TLC showed startingmaterial was consumed. The mixture was then poured into NaHCO₃(aq)carefully and the precipitate collected. The dried sample was confirmedas desired product2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine 4.

Step 3. 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine

To a solution of reactant 4 in AcOH was added reactant 5. The mixturewas stirred at 100° C. for 1 hour. TLC showed starting material wasconsumed. The mixture was then poured into water to collect theprecipitate. After washing with water, the precipitate was furthertreated with EtOAc and filtered to yield dried product the titlecompound, 2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine 6(45 mg, 63% yield). MW=360.82. ¹H NMR (300 MHz, DMSO-d₆) δ 10.25 (s,1H), 7.88 (d, J=3.9 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.23-7.29 (m, 3H),3.52 (s, 2H), 2.43 (s, 3H).

EXAMPLE 234-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-6-methyl-1,3,5-triazin-2-amine

4-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-6-methyl-1,3,5-triazin-2-aminewas prepared using2-chloro-4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazine and4-fluoroaniline by the method described for Step 3 of EXAMPLE 1 (13 mg,24% yield). MW=320.77. ¹H NMR (300 MHz, CDCl₃) δ 7.93 (d, J=4.2 Hz, 1H),7.64 (dd, J=9, 4.8 Hz, 2H), 7.11 (t, J=8.7 Hz, 2H), 7.01 (d, J=4.2 Hz,1H), 2.55 (s, 3H).

EXAMPLE 242-(4-((4-(furan-2-yl)-6-methyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(20 mg, 32% yield). MW=310.31. ¹H NMR (360 MHz, DMSO-D₆): δ 12.3 (brs,1H), 10.2 (s, 1H), 7.98 (s, 1H), 7.71 (d, J=7.1 Hz, 2H), 7.42 (s, 1H),7.21 (d, J=7.1 Hz, 2H), 6.71 (m, 1H), 3.51 (s, 2H), 2.42 (s, 3H).

EXAMPLE 252-(4-((4-(5-chlorothiophen-2-yl)-6-isopropyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(28 mg, 36% yield). MW=388.87. ¹H NMR (360 MHz, DMSO-D₆) δ 12.3 (brs,1H), 10.2 (s, 1H), 7.88 (d, J=4.0 Hz, 1H), 7.70 (d, J=8.1 Hz, 2H), 7.26(d, J=4.0 Hz, 1H), 7.22 (d, J=8.1 Hz, 2H), 3.52 (s, 2H), 2.85 (m, 1H),1.27 (d, J=6.9 Hz, 6H).

EXAMPLE 264-(5-chlorothiophen-2-yl)-N-(4-fluorophenyl)-6-isopropyl-1,3,5-triazin-2-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(32 mg, 46% yield). MW=348.82. ¹H NMR (360 MHz, CDCl₃) δ 7.87 (d, J=4.0Hz, 1H), 7.61-7.63 (m, 2H), 7.08-7.16 (m, 2H), 6.97 (d, J=4.0 Hz, 1H),2.95 (m, 1H), 1.33 (d, J=6.8 Hz, 6H).

EXAMPLE 272-(4-((4-(5-chlorothiophen-2-yl)-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(57 mg, 76% yield). MW=374.84. ¹H NMR (360 MHz, DMSO-D₆) δ 10.24 (brs,1H), 7.88 (d, J=3.7 Hz, 1H), 7.69 (d, J=8.3 Hz, 2H), 7.27 (d, J=3.7 Hz,1H), 7.22 (d, J=8.3 Hz, 2H), 3.52 (s, 2H), 2.70 (q, J=7.5 Hz, 2H), 1.26(t, J=7.5 Hz, 3H).

EXAMPLE 284-(5-chlorothiophen-2-yl)-6-ethyl-N-(4-fluorophenyl)-1,3,5-triazin-2-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(37 mg, 55% yield). MW=334.80. ¹H NMR (360 MHz, DMSO-D₆) δ 10.31 (brs,1H), 7.89 (d, J=3.9 Hz, 1H), 7.78 (m, 2H), 7.27 (d, J=3.9 Hz, 1H), 7.22(m, 2H), 2.70 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H).

EXAMPLE 294-(4-(5-chlorothiophen-2-yl)-6-isopropyl-1,3,5-triazin-2-ylamino)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(40 mg, 53% yield). MW=374.84. ¹H NMR (360 MHz, DMSO-D₆) δ 10.59 (s,1H), 7.92 (m, 5H), 7.28 (d, J=4 Hz, 1H), 2.93 (m, 1H), 1.28 (d, J=6.9Hz, 6H).

EXAMPLE 304-(4-(5-chlorothiophen-2-yl)-6-ethyl-1,3,5-triazin-2-ylamino)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(50 mg, 69% yield). MW=360.82. ¹H NMR (360 MHz, DMSO-D₆) δ 10.60 (s,1H), 7.93 (m, 5H), 7.28 (d, J=4.0 Hz, 1H), 2.74 (q, J=7.5 Hz, 2H), 1.27(t, J=7.5 Hz, 3H).

EXAMPLE 314-(4-(5-chlorothiophen-2-yl)-6-methyl-1,3,5-triazin-2-ylamino)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(50 mg, 72% yield). MW=346.79. ¹H NMR (360 MHz, DMSO-D₆) δ 10.60 (s,1H), 7.89 (m, 5H), 7.28 (d, J=4.0 Hz, 1H), 2.46 (s, 3H).

EXAMPLE 322-(4-((4-(5-chlorothiophen-2-yl)-6-propyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(30 mg, 64% yield). MW=388.87. ¹H NMR (360 MHz, DMSO-D₆) δ 12.30 (s,1H), 10.24 (s, 1H), 7.87 (d, J=3.9 Hz, 1H), 7.68 (d, J=8.4 Hz, 2H), 7.26(d, J=3.9 Hz, 1H), 7.22 (d, J=8.4 Hz, 2H), 3.53 (s, 2H), 2.64 (t, J=7.4Hz, 2H), 1.77 (m, 2H), 0.95 (t, J=7.3 Hz, 3H).

EXAMPLE 334-((4-(5-chlorothiophen-2-yl)-6-propyl-1,3,5-triazin-2-yl)amino)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (.MW=374.84. ¹H NMR (360 MHz, DMSO-D₆) δ 10.60 (s, 1H), 7.92 (m, 5H), 7.28(d, J=4.0 Hz, 1H), 2.68 (t, J=7.5 Hz, 2H), 1.79 (m, 2H), 0.96 (t, J=7.3Hz, 3H).

EXAMPLE 342-(4-(4-(5-chlorothiophen-2-yl)-6-cyclopropyl-1,3,5-triazin-2-ylamino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (9mg, 27% yield). MW=386.86. ¹H NMR (360 MHz, DMSO-D₆) δ 12.27 (s, 1H),10.12 (s, 1H), 7.85 (d, J=4.0 Hz, 1H), 7.65 (d, J=8.2 vHz, 2H), 7.25 (d,J=4.0 Hz, 1H), 7.21 (d, J=8.2 Hz, 2H), 2.0 (m, 1H), 1.09 (m, 4H).

EXAMPLE 35 methyl2-(4-((4-chloro-6-(5-chlorothiophen-2-yl)-1,3,5-triazin-2-yl)amino)phenyl)acetate

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(25 mg, 63% yield). MW=395.26. ¹H NMR (360 MHz, CDCl₃) δ 7.92 (d, J=4.1Hz, 1H) m 7.55 (d, J=8.1 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 3.70 (s, 3H),3.63 (s, 2H).

EXAMPLE 362-(4-((4-(3-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(18 mg, 65% yield). MW=380.83. ¹H NMR (360 MHz, DMSO-D₆) δ 10.18 (s,1H), 8.29 (m, 2H), 7.67 (m, 3H), 7.58 (dd, J=7.9 and 8.0 Hz, 1H), 7.23(d, J=7.7 Hz, 2H), 3.53 (s, 2H), 2.07 (m, 1H), 1.18 (m, 2H), 1.11 (m,2H).

EXAMPLE 372-(4-((4-(4-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(13 mg, 34% yield). MW=380.83. ¹H NMR (360 MHz, DMSO-D₆) δ 12.28 (s,1H), 10.14 (s, 1H), 8.34 (d, J=8.4 Hz, 2H), 7.69 (d, J=8.1 Hz, 2H), 7.61(d, 8.4 Hz, 2H), 7.22 (d, J=8.1 Hz, 2H), 3.53 (s, 2H), 2.05 (m, 1H),1.17 (m, 2H), 1.10 (m, 2H).

EXAMPLE 384-((4-(4-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(12 mg, 32% yield). MW=366.80. ¹H NMR (360 MHz, DMSO-D₆) δ 10.51 (s,1H), 8.37 (d, J=8.5 Hz, 2H), 7.93 (m, 4H), 7.62 (d, J=8.5 Hz, 2H), 2.10(m, 1H), 1.20 (m, 2H), 1.14 (m, 2H).

EXAMPLE 392-(4-((4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(38 mg, 100% yield). MW=368.82. ¹H NMR (360 MHz, DMSO-d₆) δ 10.29 (s,1H), 8.32 (m, 2H), 7.58-7.73 (m, 4H), 7.24 (d, J=7.4 Hz, 2H), 3.53 (s,2H), 2.76-2.80 (q, J=7.5 Hz, 2H), 1.30 (t, J=7.5 Hz, 3H).

EXAMPLE 404-((4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)amino)benzoic acid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(38 mg, 100% yield). MW=354.79. ¹H NMR (360 MHz, DMSO-d₆) δ 10.65 (s,1H), 8.36 (m, 2H), 7.95 (br, 4H), 7.70 (d, J=7.4 Hz, 1H), 7.61 (dd,J=7.7 and 8.2 Hz, 1H), 2.81 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.6 Hz, 3H).

EXAMPLE 414-((4-(3-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(19 mg, 70% yield). MW=366.80. ¹H NMR (360 MHz, DMSO-d₆) δ 10.54 (s,1H), 8.32 (m, 2H), 7.92 (br, 4H), 7.70 (d, J=7.7 Hz, 1H), 7.61 (dd,J=7.7 and 8.0 Hz, 1H), 2.12 (m, 1H), 1.21 (m, 2H), 1.15 (m 2H).

EXAMPLE 42

This Example is intentionally left blank.

EXAMPLE 432-(4-((4-(3-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)oxy)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(10 mg, 29% yield). MW=381.81. ¹H NMR (360 MHz, DMSO-d₆) δ 12.41 (brs,1H), 8.2 (m, 2H), 7.69 (d, J=8.2 Hz, 1H), 7.57 (dd, J=8.1 and 8.2 Hz,1H), 7.35 (d, J=8.5 Hz, 2H), 7.24 (d, J=8.5 Hz, 2H), 3.62 (s, 2H), 2.13(m, 1H), 1.16 (m, 4H).

EXAMPLE 442-(4-((4-(4-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)oxy)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(11 mg, 61% yield). MW=381.81. ¹H NMR (360 MHz, DMSO-d₆) δ 12.41 (brs,1H), 8.26 (d, J=8.5 Hz, 2H), 7.60 (d, J=8.5 Hz, 2H), 7.34 (d, J=8.4 Hz,2H), 7.24 (d, J=8.4 Hz, 2H), 3.62 (s, 2H), 2.12 (m, 1H), 1.14 (m, 4H).

EXAMPLE 454-(((4-(4-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)methyl)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(24 mg, 100% yield). MW=380.83. ¹H NMR (360 MHz, DMSO-d₆) δ 12.86 (brs,1H), 8.56 (br, 1H), 8.28 (m, 2H), 7.88 (d, J=7.5 Hz, 2H), 7.54 (m, 2H),7.42 (m, 2H), 4.66 (d, J=5.5 Hz, 1H), 4.58 (d, J=4.9 Hz, 1H), 3.35 (s,2H), 1.93 (m, 1H), 1.01 (m, 4H).

EXAMPLE 464-(((4-(3-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)methyl)benzoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(12 mg, 30% yield). MW=380.83. ¹H NMR (360 MHz, DMSO-d₆) δ 12.85 (brs,1H), 8.61 (brs, 1H), 8.25 (m, 2H), 7.88 (d, J=7.2 Hz, 2H), 7.62 (m, 1H),7.53 (m, 1H), 7.43 (m, 2H), 4.66 (d, J=5.8 Hz, 1H), 4.58 (d, J=5.8 Hz,1H), 1.96 (m, 1H), 1.02 (m, 4H).

EXAMPLE 472-(4-((4-cyclopropyl-6-(3-fluorophenyl)-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(13 mg, 38% yield). MW=364.37. ¹H NMR (360 MHz, DMSO-d₆) δ 12.28 (s,1H), 10.15 (s, 1H), 8.19 (d, J=7.8 Hz, 1H), 8.03 (m, 1H), 7.69 (d, J=8.2Hz, 2H), 7.59 (m, 1H), 7.47 (m, 1H), 7.24 (d, J=8.2 Hz, 2H), 3.53 (s,2H), 2.06 (m, 1H), 1.18 (m, 2H), 1.11 (m, 2H).

EXAMPLE 482-(4-((4-ethyl-6-(3-fluorophenyl)-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(18 mg, 37% yield). MW=352.36. ¹H NMR (360 MHz, DMSO-d₆) δ 12.29 (s,1H), 10.25 (s, 1H), 8.23 (d, J=7.8 Hz, 1H), 8.06 (m, 1H), 7.72 (d, J=8.4Hz, 2H), 7.61 (m, 1H), 7.46 (m, 1H), 7.24 (d, J=8.4 Hz, 2H), 3.53 (s,2H), 2.75 (q, J=7.5 Hz, 2H), 1.31 (t, J=7.5 Hz, 3H).

EXAMPLE 495-((6-(3-chlorophenyl)-4-cyclopropyl-4,5-dihydro-1,3,5-triazin-2-yl)amino)piperidin-2-one

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(17 mg, 81% yield). MW=345.83. ¹H NMR (360 MHz, DMSO-d₆) δ 8.28 (m, 2H),8.13 (d, J=6.9 Hz, 1H), 7.62 (m, 1H), 7.54 (m, 1H), 7.43 (brs, 1H), 4.30(m, 0.5H), 4.18 (m, 0.5H), 3.38 (m, 1H), 3.08 (m, 1H), 2.33 (m, 2H),1.96 (m, 2H), 1.80 (m, 1H), 1.11 (m, 2H), 1.06 (m, 2H).

EXAMPLE 502-(4-((4-ethyl-6-(furan-3-yl)-4,5-dihydro-1,3,5-triazin-2-yl)amino)phenyl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(19 mg, 58% yield). MW=326.35. ¹H NMR (360 MHz, DMSO-d₆) δ 12.27 (s,1H), 10.11 (s, 1H), 8.47 (brs, 1H), 7.83 (s, 1H), 7.72 (d, J=8.6 Hz,2H), 7.18 (d, J=8.6 Hz, 2H), 6.99 (s, 1H), 3.51 (s, 2H), 2.71 (q, J=7.5Hz, 2H), 1.27 (t, J=7.5 Hz, 3H).

EXAMPLE 514-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)benzonitrile

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(29 mg, 85% yield). MW=335.79. ¹H NMR (360 MHz, CDCl₃) δ 8.45 (s, 1H),8.35 (d, J=7.8 Hz, 1H), 7.88 (d, J=8.8 Hz, 2H), 7.68 (d, J=8.8 Hz, 2H),7.53 (d, J=8.0 Hz, 1H), 7.45 (dd, J=7.8 and 8.0 Hz, 1H), 2.88 (q, J=7.6Hz, 2H), 1.41 (t, J=7.6 Hz, 3H).

EXAMPLE 522-(4-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)phenyl)acetonitrile

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(35 mg, 100% yield). MW=349.82. ¹H NMR (360 MHz, CDCl₃) δ 8.44 (s, 1H),8.33 (d, J=7.7 Hz, 1H), 7.75 (d, J=8.5 Hz, 2H), 7.51 (d, J=8.0 Hz, 1H),7.43 (dd, J=7.7 and 8.0 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 3.76 (s, 2H),2.84 (q, J=7.6 Hz, 2H), 1.39 (t, J=7.6 Hz, 3H).

EXAMPLE 531-(4-((4-(3-chlorophenyl)-6-cyclopropyl-1,3,5-triazin-2-yl)amino)phenyl)imidazolidin-2-one

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(18 mg, 72% yield). MW=406.87. ¹H NMR (360 MHz, CDCl₃) δ 8.39 (s, 1H),8.30 (d, J=7.7 Hz, 1H), 7.65 (d, J=8.9 Hz, 2H), 7.47 (d, J=7.9 Hz, 1H),7.40 (dd, J=7.7 and 7.9 Hz, 1H), 3.97 (dd, J=7.5 and 8.3 Hz, 2H), 3.59(dd, J=7.5 and 8.3 Hz, 2H), 1.58 (m, 1H), 1.30 (m, 2H), 1.11 (m, 2H).

EXAMPLE 54N-(4-(2H-tetrazol-5-yl)phenyl)-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(15 mg, 79% yield). MW=378.82. ¹H NMR (360 MHz, DMSO-d₆) δ 10.62 (brs,1H), 8.35 (m, 2H), 8.04 (br, 4H), 7.69 (d, J=8.0 Hz, 1H), 7.60 (dd,J=7.8 and 8.0 Hz, 1H), 2.82 (q, J=7.5 Hz, 2H), 1.33 (t, J=7.5 Hz, 3H).

EXAMPLE 55N-(4-((2H-tetrazol-5-yl)methyl)phenyl)-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(17 mg, 85% yield). MW=392.84. ¹H NMR (360 MHz, DMSO-d₆) δ 10.30 (brs,1H), 8.31 (m, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.66 (d, J=8.1 Hz, 1H), 7.58(dd, J=7.8 and 8.1 Hz, 1H), 7.26 (d, J=8.4 Hz, 2H), 4.26 (s, 2H), 2.75(q, J=7.5 Hz, 2H), 1.29 (t, J=7.5 Hz, 3H).

EXAMPLE 56N-(4-((4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)methanesulfonylurea

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(20 mg, 51% yield). MW=404.87. ¹H NMR (360 MHz, DMSO-d₆) δ 11.94 (brs,1H), 10.64 (s, 1H), 8.36 (m, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.81 (d, J=8.8Hz, 2H), 7.70 (m, 1H), 7.61 (dd, J=8.0 and 8.1 Hz, 1H), 7.26 (br, 2H),2.81 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H).

EXAMPLE 572-(4-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)phenyl)acetamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(7.6 mg, 48% yield). MW=367.83. ¹H NMR (360 MHz, CDCl₃) δ 8.44 (s, 1H),8.35 (d, J=7.7 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 7.50 (m, 1H), 7.42 (dd,J=7.7 and 8.0 Hz, 1H), 7.32 (d, J=8.4 Hz, 2H), 5.40 (br, 2H), 3.59 (s,2H), 2.84 (q, J=7.5 Hz, 2H), 1.39 (t, J=7.5 Hz, 3H).

EXAMPLE 582-(4-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)phenyl)ethanol

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (8mg, 21% yield). MW=354.83. ¹H NMR (360 MHz, CDCl₃) δ 8.46 (s, 1H), 8.35(d, J=7.6 Hz, 1H), 7.66 (d, J=8.4 Hz, 2H), 7.50 (m, 1H), 7.43 (dd, J=7.6and 7.8 Hz, 1H), 7.28 (d, J=8.4 Hz, 2H), 3.89 (m, 2H), 2.89 (m, 4H),1.40 (t, J=7.5 Hz, 3H).

EXAMPLE 592-(4-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)phenyl)propanoicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (7mg, 18% yield). MW=382.84. ¹H NMR (360 MHz, DMSO-d₆) δ 12.26 (s, 1H),10.28 (s, 1H), 8.32 (m, 2H), 7.73 (d, J=8.4 Hz, 2H), 7.68 (d, J=7.7 Hz,1H), 7.60 (dd, J=7.7 and 7.9 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 3.64 (q,J=7.1 Hz, 1H), 2.76 (q, J=7.5 Hz, 2H), 1.35 (d, J=7.1 Hz, 3H), 1.30 (t,J=7.5 Hz, 3H).

EXAMPLE 602-(4-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)phenyl)-2-methylpropanoic

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(20 mg, 50% yield). MW=396.87. ¹H NMR (360 MHz, CDCl₃) δ 8.45 (brs, 1H),8.35 (d, J=7.6 Hz, 1H), 7.72 (d, J=8.6 Hz, 2H), 7.51 (d, J=8.1 Hz, 1H),7.46 (d, J=8.6 Hz, 2H), 7.43 (dd, J=7.6 and 8.1 Hz, 1H), 2.81 (q, J=7.5Hz, 2H), 1.39 (t, J=7.5 Hz, 3H).

EXAMPLE 612-(4-((4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)oxy)phenyl)acetamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(18 mg, 49% yield). MW=368.82. ¹H NMR (360 MHz, DMSO-d₆) δ 8.24 (m, 2H),7.71 (d, J=7.7 Hz, 1H), 7.59 (dd, J=7.7 and 8.2 Hz, 1H), 7.51 (brs, 1H),7.35 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.4 Hz, 2H), 6.93 (brs, 1H), 3.42 (s,2H), 2.83 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).

EXAMPLE 624-(4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-ylamino)benzamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(20 mg, 57% yield). MW=353.80. ¹H NMR (360 MHz, DMSO-d₆) δ 10.53 (s,1H), 8.35 (m, 2H), 7.89 (br, 4H), 7.70 (d, J=7.7 Hz, 2H), 7.61 (dd,J=7.8 and 8.0 Hz, 1H), 7.26 (brs, 2H), 2.82 (q, J=7.5 Hz, 2H), 1.32 (t,J=7.5 Hz, 3H).

EXAMPLE 634-((4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)oxy)benzamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(10 mg, 29% yield). MW=354.79. ¹H NMR (360 MHz, DMSO-d₆) δ 8.23 (m, 2H),8.03 (s, 1H), 7.96 (d, J=8.6 Hz, 2H), 7.70 (d, J=7.7 Hz, 1H), 7.58 (dd,J=7.7 and 7.9 Hz, 1H), 7.42 (s, 1H), 7.40 (d, J=8.6 Hz, 2H), 2.84 (q,J=7.5 Hz, 2H), 1.25 (t, J=7.5 Hz, 3H).

EXAMPLE 642-(4-((4-(3-chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)amino)piperidin-1-yl)aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(60 mg, 100% yield as HCl salt). MW=412.31. ¹H NMR (360 MHz, DMSO-d₆) δ10.40 (brs, 1H), 8.31 (m, 2H), 8.26 (d, J=7.9 Hz, 1H), 7.65 (m, 1H),7.55 (dd, J=7.6 and 7.9 Hz, 1H), 4.10 (s, 2H), 3.67 (m, 1H), 2.65 (m,2H), 2.11 (m, 2H), 1.94 (m, 2H), 1.25 (m, 3H).

EXAMPLE 652-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetamide

Step 1. Methyl 2-(4-(bromomethyl)phenyl)acetate

To a stirred suspension of 2-(4-(bromomethyl)phenyl)acetic acid (5.00 g,21.8 mmol, 1.0 eq.) in methanol (75 mL) was added chlorotrimethylsilane(0.64 mL, 5.02 mmol, 0.23 eq.) at room temperature. The resultingmixture was stirred at room temperature for 2 hr, at which time thereaction was a clear colorless solution. The volatile material wasremoved under reduced pressure, the residue dissolved in methanol (25mL), and the volatile material was removed under reduced pressure. Thisprocess was repeated two additional times to afford methyl2-(4-(bromomethyl)phenyl)acetate as an orange solid (5.30 g,quantitative yield). ¹H NMR (CDCl₃, 500 MHz) δ 7.37-7.33 (m, 2H),7.26-7.24 (m, 2H), 4.48 (s, 2H), 3.69 (s, 3H), 3.62 (s, 2H). [Lit. J.Med. Chem. 2009, 52, 1180-9.]

Step 2. Methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate

A 250-mL round bottom flask, with stirrer bar, was charged with2-(4-(bromomethyl)phenyl)acetate (3.45 g, 14.2 mmol, 1.0 eq.), pinacoldiborane (4.32 g, 17.0 mmol, 1.2 eq.),tetrakis(triphenylphosphine)palladium(0) (1.64 g, 1.42 mmol, 0.10 eq.),and K₂CO₃ (5.88 g, 42.6 mmol, 3.0 eq.). Dioxane (80 mL) was added. Theresulting mixture was stirred under Ar at 80° C. for 23 hrs. Aftercooling to room temperature, the reaction was diluted with ethyl acetate(200 mL) and then filtered through celite. The filtrate was washed withsat. sodium chloride (3×25 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue (9.5 g) was purified bychromatography on silica gel using hexane/ethyl acetate (10:0 to 0:10)as eluent to afford methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(2.88 g, 70% yield) as a colorless semisolid. ¹H NMR (CDCl₃, 500 MHz) δ7.14 (s, 4H), 3.67 (s, 3H), 3.57 (s, 2H), 2.27 (s, 2H), 1.23 (s, 12H).

Step 3. Methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate

A 50-mL flask, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (870 mg, 3.44 mol, 1 eq.),methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(1.00 g, 3.44 mmol, 1 eq.), Pd(dppf)Cl₂ (280 mg, 0.34 mmol, 0.10 eq.),and powdered Na₂CO₃ (1.09 g, 10.3 mmol, 3.0 eq.). Dioxane (16 mL) andwater (8 mL) were added. The resulting mixture was stirred under Ar at90° C. for 2 hr. until the starting chloride was consumed. After coolingto room temperature, the reaction mixture was filtered through celitewashing with ethyl acetate until the filtrate was colorless. Thefiltrate was washed with sat. sodium chloride (3×25 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue (1.8 g) was purified by chromatography on silica gel usinghexane/dichloromethane (10:0 to 0:10) as eluent, followed bychromatography on silica gel using hexane/ethyl acetate (10:0 to 3:1) aseluent, to afford methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate(0.65 g, 50% yield) as a colorless oil. MW=380.87. ¹H NMR (CDCl₃, 500MHz) δ 8.49-8.47 (m, 1H), 8.37 (dt, J=7.5, 1.5 Hz, 1H), 7.44-7.38 (m,2H), 7.31-7.27 (m, 2H), 7.27-7.23 (m, 2H, overlaps with CDCl₃), 6.85 (s,1H), 4.10 (s, 2H), 3.69 (s, 3H), 3.61 (s, 2H), 2.76 (q, J=7.5 Hz, 2H),1.31 (t, J=7.5 Hz, 3H).

Step 4.2-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetamide

A 20-mL vial was charged with methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate(113 mg, 0.30 mmol, 1.0 eq.) and ammonium chloride (48 mg, 0.89 mmol,3.0 eq.). To this was added methanol (3 mL) followed by NH₃ (7.5 mL, 7Nin methanol, 53 mmol, 177 eq.). The vial was sealed and the resultingmixture was stirred at 100° C. for 43 hr. The crude reaction solutionwas adsorbed onto silica then purified by chromatography on silica gelusing dichloromethane/methanol (0 to 5%) as eluent, followed bychromatography on silica gel using hexane/ethyl acetate (100:0 to 0:100)as eluent, to give2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetamide(37 mg, 35% yield) as a white solid. MW=365.86. ¹H NMR (DMSO-d₆, 500MHz) δ 8.38-8.33 (m, 2H), 7.61-7.53 (m, 2H), 7.41 (br s, 1H), 7.29 (d,J=8.0 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H),4.09 (s, 2H), 3.32 (s, 2H), 2.77 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz,3H).

EXAMPLE 662-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)aceticacid

A 25-mL flask, with stirrer bar, was charged with methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate(64 mg, 0.17 mmol, 1.0 eq.) and THF (3 mL). Water (3 mL) and LiOH.H₂O(21 mg, 0.50 mmol, 3.0 eq.) were added. The resulting mixture wasstirred at room temperature for 17 hrs until the starting ester wasconsumed. The reaction mixture was diluted with water (10 mL) andacidified with 2N HCl. The mixture was extracted with ethyl acetate. Theorganic extract was washed with sat. sodium chloride (5 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue (88 mg) was purified by chromatography on silica gel usingdichloromethane/methanol (10:0 to 9:1) as eluent to afford2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)aceticacid (40 mg, 66% yield) as a white solid. MW=366.84. ¹H NMR (DMSO-d₆,500 MHz) δ 12.31 (br s, 1H), 8.40-8.33 (m, 2H), 7.62-7.53 (m, 2H), 7.31(d, J=8.0 Hz, 2H), 7.26 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 4.10 (s, 2H),3.51 (s, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).

EXAMPLE 672-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)ethanol

A 25-mL flask, with stirrer bar, was charged with methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate(52 mg, 0.13 mmol, 1.0 eq.) and THF (3 mL). The flask was cooled to 0°C. under nitrogen. A solution of 1M LiAlH₄ in THF (0.31 mL, 0.31 mmol,2.3 eq.) was added and the reaction was allowed to slowly warm to roomtemperature. After 4.5 hrs, the reaction mixture was quenched withmethanol, diluted with water (10 mL), and acidified with 2N HCl to pH˜3. The mixture was extracted with ethyl acetate (3×12 mL). The organicextract was washed with sat. sodium chloride (5 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residue(49 mg) was purified by chromatography on silica gel using hexanes/ethylacetate (1:0 to 1:1) as eluent to afford2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)ethanol(17 mg, 36% yield) as a colorless oil. MW=352.86. ¹H NMR (DMSO-d₆, 500MHz) δ 8.38-8.33 (m, 2H), 7.61-7.53 (m, 2H), 7.28-7.25 (m, 3H), 7.16 (d,J=8.0 Hz, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.08 (s, 2H), 3.60-3.53 (m, 2H),2.77 (q, J=7.5 Hz, 2H), 2.67 (t, J=7.0 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H).

EXAMPLE 682-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetamide

Step 1. Methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetate

A 20-mL vial, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (318mg, 1.20 mol, 1.0 eq.), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(350 mg, 1.20 mmol, 1.0 eq.), Pd(dppf)Cl₂ (98 mg, 0.12 mmol, 0.10 eq.),and powdered Na₂CO₃ (383 mg, 3.61 mmol, 3.0 eq.). Dioxane (8 mL) andwater (4 mL) were added. The resulting mixture was stirred under Ar at90° C. for 3.5 hrs until the starting chloride was consumed. Aftercooling to room temperature, the reaction mixture was filtered throughcelite washing with ethyl acetate until the filtrate was colorless. Thefiltrate was washed with sat. sodium chloride (3×10 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue (592 mg) was purified by chromatography on silica gel usinghexane/ethyl acetate (1:0 to 3:1) as eluent, to afford methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetate(98 mg, 21% yield) as a colorless oil. MW=392.88. ¹H NMR (CDCl₃, 500MHz) δ 8.46-8.44 (m, 1H), 8.35 (m, 1H), 7.43-7.36 (m, 2H), 7.27 (d,J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 4.09 (s, 2H), 3.68 (s, 3H), 3.59(s, 2H), 3.02 (t, J=8.0 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.11 (quintet,J=7.5 Hz, 2H).

Step 2.2-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetamide

A 20-mL vial was charged with methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetate(98 mg, 0.25 mmol, 1.0 eq.) and ammonium chloride (40 mg, 0.75 mmol, 3.0eq.). Methanol (3 mL) was added to the mixture followed by NH₃ (7.1 mL,7N in methanol, 50 mmol, 200 eq.). The vial was sealed and the resultingmixture was stirred at 100° C. for 40 hr. The crude reaction solutionwas adsorbed onto silica, then purified by chromatography on silica gelusing dichloromethane/methanol (0 to 10%) as eluent, to give2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)methyl)phenyl)acetamide(67 mg, 71% yield) as a white solid. MW=377.87. ¹H NMR (DMSO-d₆, 500MHz) δ 8.36-8.31 (m, 2H), 7.57-7.51 (m, 2H), 7.40 (br s, 1H), 7.25 (d,J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.08 (s, 2H),3.31 (s, 2H), 2.97 (t, J=8.0 Hz, 2H), 2.90 (t, J=7.5 Hz, 3H), 2.07(quintet, J=7.5 Hz, 2H).

EXAMPLE 692-(3-Chlorophenyl)-4-(4-methylbenzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A 25-mL round bottom flask, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (318mg, 1.20 mol, 1.0 eq.) and Fe(acac)₃ (6.6 mg, 19 μmol, 0.05 eq.), NMP(0.4 mL) and THF (4.0 mL). The mixture was cooled to 0° C. undernitrogen. A solution of 4-methylbenzymagnesium chloride (0.83 mL, 0.5Min THF, 0.41 mmol, 1.1 eq.) was added dropwise over 2 minutes. Theresulting mixture was stirred 0° C. for 1.5 hr until the startingchloride was consumed. The reaction was quenched with a 9:1 sat.NH₄Cl/conc. NH₄OH solution (10 mL) then diluted with ethyl acetate (75mL). The organic layer was washed with sat. sodium chloride (3×5 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue (175 mg) was purified by chromatography on silicagel using dichloromethane as the eluent, to afford2-(3-chlorophenyl)-4-(4-methylbenzyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(65 mg, 52% yield) as a white solid. MW=334.84. ¹H NMR (DMSO-d₆, 500MHz) δ 8.35-8.30 (m, 2H), 7.58-7.51 (m, 2H), 7.20 (d, J=8.0 Hz, 2H),7.11 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.88 (t,J=7.5 Hz, 2H), 2.25 (s, 3H), 2.06 (quintet, J=7.5 Hz, 2H).

EXAMPLE 70(2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(p-tolyl)methanone

Step 1.2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbonitrile

A 10-mL microwave vial, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (250mg, 0.94 mmol, 1.0 eq.), zinc cyanide (221 mg, 1.88 mmol, 2.0 eq.),tetrakis(triphenylphosphine)palladium(0) (109 mg, 0.094 mmol, 0.10 eq.)and THF (5 mL). The resulting mixture was subjected to microwaveirradiation at 165° C. under Ar for 30 min. The cooled reaction mixturewas preabsorbed onto silica gel and purified by chromatography on silicagel using hexane/ethyl acetate (10:0 to 7:3) as eluent to afford2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine-4-carbonitrile(205 mg, 85% yield) as a white solid. MW=255.70. ¹H NMR (CDCl₃, 500 MHz)δ 8.46-8.42 (m, 1H), 8.35-8.30 (m, 1H), 7.49-7.46 (m, 1H), 7.45-7.40 (m,1H), 3.21-3.14 (m, 4H), 2.29 (quintet, J=8.0 Hz, 2H).

Step 2:(2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(p-tolyl)methanone

A 25-mL round bottom flask, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (97mg, 0.38 mol, 1.0 eq.) and THF (5.0 mL). A solution of 4-tolylmagnesiumbromide (1.14 mL, 1.0M in THF, 1.14 mmol, 3.0 eq.) was added dropwiseover 1 minute at room temperature. After stirring for 2 hrs at roomtemperature the reaction was heated to reflux for 2.5 hrs. The reactionwas cooled to room temperature and was quenched with 2N HCl and dilutedwith ethyl acetate (50 mL). The organic layer was washed with sat.sodium chloride (3×5 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue (227 mg) was purifiedby chromatography on silica gel using hexanes/ethyl acetate (10:0 to8:2) as the eluent, to afford(2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(p-tolyl)methanone(49 mg, 37% yield) as a yellow solid. MW=348.83. ¹H NMR (DMSO-d₆, 500MHz) δ 8.31-8.26 (m, 2H), 7.29 (d, J=8.5 Hz, 2H), 7.62-7.53 (m, 2H),7.41 (d, J=8.0 Hz, 2H), 3.12 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.0 Hz, 2H),2.43 (s, 3H), 2.06 (quintet, J=7.5 Hz, 2H).

EXAMPLE 712-(5-chloro-2-thienyl)-5-ethyl-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-6-methyl-pyrimidin-4-amine

Step 1, 2-(5-chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one

A 100-mL round bottomed flask was charged with5-chlorothiophene-2-carboxamidine HCl salt (394 mg, 2 mmol, 1 eq.),ethyl 2-ethyl-3-oxo-butanoate (950 mg, 6 mmol, 3 eq.), and ethanol (10ml). To the mixture was added sodium methoxide (25 w % in methanol, 1.73g, 8 mmol, 3 eq.). The resulting mixture was stirred under reflux for 7hr. After cooling to room temperature, the mixture was evaporated underreduced pressure to dryness and the residue was treated with 2N HCl (4.5ml). Solid was collected by filtration and washed with water followed byhexane. The product thus obtained was forwarded to the next step withoutany further purification (240 mg, 47% yield).

Step 2, 4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine

A 18-mL vial was charged with2-(5-chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one

(510 mg, 2 mmol). POCl₃ (2.5 ml) was added. The resulting mixture wasstirred at 90 C for 4 hr. After cooling to room temperature, the mixturewas added dropwise slowly to cold NaHCO₃ aq. Dichloromethane was added.The organic layer was separated and passed through a plug of silica gel,using dichloromethane as eluent to give4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (283 mg, 52%yield).

Step 3,2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzoicacid

A 18-mL vial was charged with4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (87 mg,0.318 mmol, 1.05 eq.), 5-amino-2-bromo-benzoic acid (65 mg, 0.3 mmol, 1eq.). AcOH (1 ml) and 4 N HCl in dioxane (5 drops). The resultingmixture was stirred under Ar at 110° C. for 2 hr. After cooling to rt,The volatile material was removed under reduced pressure and the residuewas treated with dichloromethane to give the title compound (105 mg, 77%yield).

Step 4,[2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methanol

A 100-mL round bottomed flask was charged with2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzoicacid (impure, obtained from several reactions on 1.3 mmol scale.), THF(20 ml). To the mixture was added BH₃ (1N in THF, 7.5 ml). The resultingmixture was stirred at rt overnight. Then treated with 2N HCl aq. (10ml) followed by sodium bicarbonate to pH=7. The mixture was extractedwith ethyl acetate (3×10 ml). The organic layers were combined and driedover Na₂SO₄. Removal of solvent gave a residue, which was purified bychromatography on silica gel using 0.5% of methanol in dichloromethaneto give the title compound (198 mg, 35% yield).

Step 5,[2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methylacetate

A 18-mL vial was charged with[2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methanol(93 mg, 0.21 mmol), acetyl chloride (100 mg, 1.27 mmol, 6 eq.). Pyridine(1 ml) was added followed by 4-(dimethylamino)pyridine (5 mg, 0.2 eq.).The resulting mixture was stirred at rt for 2 hr. Then water was (5 ml)added. The precipitate was collected and washed with water. The crudeproduct was purified by chromatography on silica gel usingdichloromethane as eluent to give the tile compound (73 mg, 72% yield).

Step 6,[5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylacetate

A 18-mL vial was charged with[2-bromo-5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methylacetate (34 mg, 0.064 mmol, 1 eq.),4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane(20 mg, 0.077 mmol, 1.2 eq.), Pd(dppf)₂Cl₂ (6 mg, 0.11 eq.), KOAc (0.21mmol, 3 eq.) and dioxane (2 ml). The resulting mixture was stirred underAr at 95° C. for 4.5 hr. After cooling to rt, the volatile material wasremoved under reduced pressure and the residue was purified bychromatography on silica gel using dichloromethane as eluent to give thetitle compound (16.3 mg, 49% yield).

Step 7,2-(5-chloro-2-thienyl)-5-ethyl-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-6-methyl-pyrimidin-4-amine

A 18-mL vial was charged with[5-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methylacetate (8.6 mg, 0.016 mmol) and lithium hydroxide (10 mg, 0.23 mmol).THF (1 ml), MeOH (0.2 ml) and water (0.2 ml) was added to the vial. Theresulting mixture was stirred at rt overnight. Then the volatilematerial was removed. The residue was treated with THF (0.5 ml) and 2NHCl aq. (0.5 ml) for 1 hr. The mixture was neutralized by addition ofNaHCO₃ aq. to pH=7. Then the mixture was extracted with ethyl acetate(3×2 ml). The ethyl acetate layers were combined and solvent was removedto dryness and the residue was purified by chromatography on silica gelusing DCM followed by 0.4% MeOH in DCM as eluent to afford2-(5-chloro-2-thienyl)-5-ethyl-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-6-methyl-pyrimidin-4-amine(4.2 mg, 68% yield). MW=385.68. ¹H NMR (CDCl₃, 400 MHz) δ 7.98 (s, 1H),7.75 (d, J=8.0 Hz, 1H), 7.67 (d, J=4.0 Hz, 1H), 7.48 (d, J=8.0 Hz, 1H),6.95 (d, J=4.0 Hz, 1H), 6.68 (brs, 1H), 5.18 (S, 2H), 2.68 (q, J=8.0 Hz,2H), 2.51 (s, 3H), 1.27 (t, J=8.0 Hz, 3H).

EXAMPLE 722-(5-Chloro-2-thienyl)-5-ethyl-N-(1-hydroxy-3H-2,1-benzoxaborol-6-yl)-6-methyl-pyrimidin-4-amine

A 8-mL vial was charged with[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (20 mg, 0.052 mmol, 1.05 eq.),1-hydroxy-3H-2,1-benzoxaborol-6-amine (7.5 mg, 0.05 mmol, 1 eq.) andDMSO (0.5 ml). The mixture was stirred at 90° C. under Ar for 2 hr.After cooling to room temperature, the mixture was added to water (5ml). The precipitate was collected by filtration and washed with water.After dried, the mixture was purified by prep. TLC using 10% of ethylacetate in dichloromethane as a mobile phase to give the title compoundas a solid (10 mg, 52% yield). MW=385.68. ¹H NMR (400 MHz, CDCl₃) δ 7.96(d, J=7.2 Hz, 1H), 7.85 (s, 1H), 7.65 (d, J=4.0 Hz, 1H), 7.41 (d, J=7.2Hz, 1H), 6.92 (d, J=4.0 Hz, 1H), 6.58 (brs, 1H), 5.15 (s, 1H), 2.65 (q,J=7.6 Hz, 2H), 2.50 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).

EXAMPLE 732-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidin-4-amine

Step 1, 5-Chlorothiophene-2-carboxamidine HCl salt

Synthesis of the title compound was described in step 1 of EXAMPLE 9.

Step 2, 2-(5-Chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one

A 250-mL round bottomed flask was charged with5-chlorothiophene-2-carboxamidine HCl salt (6.81 g, 34.6 mmol, 1 eq.),ethyl 2-ethyl-3-oxo-butanoate (12 g, 72 mmol, 2 eq.), and ethanol (100ml). To the mixture was added sodium methoxide (25 w % in methanol, 23g, 107 mmol, 3 eq.). The resulting mixture was stirred under reflux for7 hr. After cooling to room temperature, the mixture was evaporatedunder reduced pressure to dryness and the residue was treated with 2NHCl (60 ml). Solid was collected by filtration and washed with waterfollowed by ether. The product thus obtained was forwarded to the nextstep without any further purification (4.53 g, 51% yield).

Step 3, 4-Chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine

An 100-mL round bottomed flask was charged2-(5-Chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one (4 g, 15.7mmol). POCl₃ (16 ml) was added. The resulting mixture was stirred at 90C for 6 hr. After cooling to room temperature, the volatile material wasremoved under reduced pressure and the residue was with NaHCO₃ aq (100ml). Dichloromethane was added. The organic layer was separated andpassed through a plug of silica gel, using dichloromethane as eluent togive the title compound as a solid (2.82 g, 66% yield).

Step 4,2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile

An 18-mL vial was charged4-Chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (60 mg, 0.22mmol, 1.07 eq.), 4-aminophenyl)acetonitrile (27 mg, 0.205 mmol, 1 eq.),and AcOH (1 ml). To the mixture was added HCl (4 N in dioxane, 5 drops).The resulting mixture was stirred at 110° C. for 2 hr. After cooling tort, the reaction mixture was added to NaHCO₃ aq (20 ml). The mixture wasextracted with dichloromethane. The organic layer was separated andpassed through a plug of silica gel, using dichloromethane as eluent togive the title compound as a white solid (36 mg, 48% yield).

Step5,2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidin-4-amine(T-098)

In an 4-mL was charged with2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile(16 mg, 0.043 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) andtetrabutylammonium fluoride trihydrate (20 mg, 0.057 mmol). The mixturewas stirred at 110° C. overnight. After cooling to room temperature, themixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml)was added. The precipitate was collected by filtration and washed withwater (5 ml) followed dichloromethane (5 ml). After dried, the titlecompound was obtained as a solid (13 mg, 71% yield, HCl salt, it isregioisomers). MW/HCl=448.41. ¹H NMR (DMSO-D₆, 360 MHz) δ 8.0 (s, brs,1H), 7.63 (d, J=7.6 Hz, 2H), 7.32 (d, J=7.6 Hz, 1H), 7.27 (d, J=3.6 Hz,1H), 4.32 (s, 2H), 2.74 (q, J=6.8 Hz, 2H), 2.50 (s, 3H), 1.11 (t, J=6.8Hz, 2H). MS: ESI⁺, m/z 412 [M+H]⁺. LCMS: 98.6%.

EXAMPLE 742-(5-Chloro-2-thienyl)-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

Step1,2-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetonitrile

Synthesis of the title compound was described in EXAMPLE 18.

Step 2,2-(5-Chloro-2-thienyl)-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(T-101)

In an 4-mL was charged with2-[4-[[2-(5-Chloro-2-thienyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl]amino]phenyl]acetonitrile(20 mg, 0.055 mmol), azidotrimethylsilane (80 mg, 1.44 mmol) andtetrabutylammonium fluoride trihydrate (25 mg, 0.07 mmol). The mixturewas stirred at 110° C. overnight. After cooling to room temperature, themixture was dissolved in dichloromethane (2 ml) and 2N HCl (aq.) (1 ml)was added. The precipitate was collected by filtration and washed withwater (5 ml) followed dichloromethane (5 ml). The solid thus obtainedwas further triturated with dichloromethane (4 ml) to give the titlecompound (11 mg, 45% yield, HCl salt, it is regioisomers).MW/HCl=446.36. ¹H NMR (DMSO-D₆, 360 MHz) δ 7.76 (m, 3H), 7.30 (d, J=7.9Hz, 2H), 7.23 (d, J=3.6 Hz, 1H), 4.29 (s, 2H), 2.92 (t, J=6.8 Hz, 2H),2.86 (t, J=6.8 Hz, 2H), 2.11 (t, J=6.8 Hz, 2H). MS: ESI⁺, m/z 410[M+H]⁺. LCMS: 97%.

EXAMPLE 752-(3-Chlorophenyl)-N-[4-(1H-tetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(17 mg, 77% yield, HCl salt). MW/HCl=426.34. ¹H NMR (400 MHz, DMSO-D₆) δ9.65 (brs, 1H), 8.31 (s, 1H), 8.26 (m, 1H), 8.12-8.05 (m, 4H), 7.67-7.64(m, 2H), 3.04-2.95 (m, 4H), 2.19-2.15 (m, 2H).

EXAMPLE 762-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(1H-tetrazol-5-yl)phenyl]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(4.5 mg, 23% yield, HCl salt). MW/HCl=434.34. ¹H NMR (400 MHz,Methanol-D₄) δ 8.03 (d, J=8.8 Hz, 2H), 7.98 (d, J=8.8 Hz, 2H), 7.7 (d,J=4.0 Hz, 1H), 7.02 (d, J=4.0 Hz, 1H), 2.79 (q, J=7.2 Hz, 2H), 2.51 (s,3H), 1.23 (t, J=7.2 Hz, 3H).

EXAMPLE 772-(5-Chloro-2-thienyl)-N-[4-(1H-tetrazol-5-yl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(18 mg, 73% yield, HCl salt). MW/HCl=432.33. ¹H NMR (400 MHz, DMSO-D₆) δ9.21 (brs, 1H), 8.07-8.04 (m, 4H), 7.70 (d, J=4.0 Hz, 1H), 7.20 (d,J=4.0 Hz, 1H), 2.91-2.88 (m, 4H), 2.12-2.08 (m, 2H).

EXAMPLE 782-(3-Chlorophenyl)-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(17 mg, 70% yield, HCl salt). MW/HCl=440.33. ¹H NMR (400 MHz, DMSO-D₆) δ9.50 (brs, 1H), 8.25 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 7.74 (d, J=8.8 Hz,2H), 7.62-7.58 (m, 2H), 7.32 (d, J=8.8 Hz, 2H), 3.0 (t, J=6.8 Hz, 2H),2.91 (t, J=6.8 Hz, 2H), 2.15 (m, 2H).

EXAMPLE 792-(5-Chloro-2-thienyl)-N-[4-(2H-tetrazol-5-ylmethyl)phenyl]-6-(trifluoromethyl)pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (6mg, 67% yield, HCl salt). MW/HCl=474.29. ¹H NMR (400 MHz, Methanol-D₄) δ7.79 (d, J=4.0 Hz, 1H), 7.75 (d, brs, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.06(d, J=4.0 Hz, 1H), 6.89 (s, 1H), 4.35 (s, 2H).

EXAMPLE 80(4-((4-(3-Chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)methanol

Step 1. Preparation of methyl 3-chlorobenzimidate

To a solution of 3-chlorobenzonitrile (4.0 g, 29.1 mmol) in methanol (30mL) was added sodium methoxide (0.16 g, 2.9 mmol). The mixture stirredat rt for 2 d, diluted with water, and extracted with methylenechloride. The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (2.32 g, 47%) as a clear oil. MW=169.61. ¹HNMR (CDCl₃, 500 MHz) δ 7.85 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H),7.46-7.42 (m, 1H), 7.35 (t, J=7.9 Hz, 1H), 3.94 (s, 3H); APCI MS m/z 170[M+H]⁺.

Step 2. Preparation of 3-chloro-N-cyanobenzimidamide

To a solution of methyl 3-chlorobenzimidate (2.3 g, 13.6 mmol) inmethanol (25 mL) was added cyanamide (0.572 g, 13.6 mmol). The mixturewas stirred at rt for 16 h resulting in a thick white suspension. Themixture was filtered and dried under vacuum and heat to give 1.83 g of awhite solid. The filtrate was purified by column chromatography (silica,hexanes/ethyl acetate) to give 0.350 g of white solid. Both batches werecombined to afford the title compound (2.18 g, 89%) as a white solid.MW=179.61. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.20 (s, 1H), 8.78 (br s, 1H),8.04-7.82 (m, 2H), 7.71-7.66 (m, 1H), 7.54 (t, J=8.0 Hz, 1H); APCI MSm/z 180 [M+H]⁺.

Step 3. Preparation of2-chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine

To a suspension of 3-chloro-N-cyanobenzimidamide (1.4 g, 7.8 mmol) wasadded N,N-dimethylpropionamide (0.790 g, 7.8 mmol) and POCl₃ (1.8 mL,19.5 mmol). The mixture was heated to 70° C. for 16 h. The reaction wascooled, diluted with saturated aqueous sodium bicarbonate, and extractedwith hexanes. The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/dichloromethane) toafford the title compound (1.41 g, 71%) as an off-white solid.MW=254.12. ¹H NMR (CDCl₃, 500 MHz) δ 8.53-8.50 (m, 1H), 8.44-8.40 (m,1H), 7.59-7.56 (m, 1H), 7.46 (t, J=8.0 Hz, 1H) 2.99 (q, J=7.5 Hz, 2H),1.43 (t, J=7.5 Hz, 3H); APCI MS m/z 254 [M+H]⁺.

EXAMPLE 80(4-((4-(3-Chlorophenyl)-6-ethyl-1,3,5-triazin-yl)amino)phenyl)methanol

2-Chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.140 g, 0.55 mmol)and 4-aminobenzyl alcohol (0.135 g, 1.1 mmol) were suspended in aceticacid (5 mL). The mixture was heated to 75° C. for 1 h. The reaction wascooled, diluted with saturated aqueous sodium bicarbonate, and extractedwith ethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by column chromatography (silica, dichloromethane/ethylacetate) and then triturated with hexanes to afford the title compound(0.030 g, 16%) as a yellow solid. MW=340.81. ¹H NMR (DMSO-d₆, 500 MHz) δ10.24 (s, 1H), 8.42-8.31 (m, 2H), 7.75-7.68 (m, 3H), 7.61 (t, J=7.5 Hz,1H), 7.36-7.28 (m, 2H), 5.11 (t, J=5.5 Hz, 1H), 4.48 (d, J=5.5 Hz, 2H),2.78 (q, J=7.5 Hz, 2H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 341 [M+H]⁺.

EXAMPLE 813-(4-((4-(3-Chlorophenyl)-6-ethyl-1,3,5-triazin-2-yl)amino)phenyl)propan-1-ol

2-Chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.150 g, 0.59 mmol)and 3-(4-aminophenyl)propan-1-ol (0.130 g, 0.89 mmol) were suspended inacetic acid (5 mL). The mixture was heated to 75° C. for 2 h. After thistime, the reaction was cooled, diluted with saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The combined organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the titlecompound (0.077 g, 35%) as a yellow solid. MW=368.86. ¹H NMR (DMSO-d₆,500 MHz) δ 10.19 (s, 1H), 8.41-8.31 (m, 2H), 7.71-7.67 (m, 3H), 7.60 (t,J=8.0 Hz, 1H), 7.24-7.16 (m, 2H), 4.45 (t, J=5.5 Hz, 1H), 3.43 (q, J=5.5Hz, 2H), 2.77 (q, J=7.5 Hz, 2H), 2.60 (t, J=7.5 Hz, 2H), 2.51-2.49 (m,2H), 1.75-1.69 (m, 2H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 369 [M+H]⁺.

EXAMPLE 824-(3-Chlorophenyl)-6-ethyl-N-(4-(2-methoxyethyl)phenyl)-1,3,5-triazin-2-amine

A mixture of 2-chloro-4-(3-chlorophenyl)-6-ethyl-1,3,5-triazine (0.105g, 0.41 mmol) and 4-(2-methoxyethyl)aniline (0.075 g, 0.49 mmol) weresuspended in acetic acid (1 mL) and the mixture was heated at 75° C. for3 h. After this time, the reaction was cooled, diluted with saturatedaqueous sodium bicarbonate, and extracted with ethyl acetate. Thecombined organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.094 g, 62%) as a white solid. MW=368.86. ¹H NMR(DMSO-d₆, 500 MHz) δ 10.21 (s, 1H), 8.41-8.30 (m, 2H), 7.72-7.68 (m,3H), 7.61 (t, J=7.5 Hz, 1H), 7.27-7.19 (m, 2H), 3.54 (t, J=7.0 Hz, 2H),3.25 (s, 3H), 2.80-2.75 (m, 4H), 1.32 (t, J=7.5 Hz, 3H); APCI MS m/z 369[M+H]⁺.

EXAMPLE 83 2-(4-((2-(3-Chlorophenyl)pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of 4-chloro-2-(3-chlorophenyl)pyridine hydrochloride

Following general procedure F, 2,4-dichloropyridine (4.0 g, 27 mmol) wasreacted with (3-chlorophenyl)boronic acid (4.6 g, 30 mmol), followed byformation of the hydrochloride salt to afford the title compound (5.0 g,71%) as a white solid. MW=260.55. ¹H NMR (CDCl₃, 500 MHz) δ 8.92-8.79(m, 1H), 8.16-8.09 (m, 1H), 8.03 (s, 1H), 7.95 (s, 1H), 7.74-7.64 (m,1H), 7.58-7.52 (m, 2H); APCI MS m/z 224 [M+H]⁺.

EXAMPLE 83 2-(4-((2-(3-Chlorophenyl)pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure A2, 4-chloro-2-(3-chlorophenyl)pyridinehydrochloride (0.115 g, 0.44 mmol) was reacted with2-(4-aminophenyl)acetamide (0.080 g, 0.53 mmol), followed by formationof the hydrochloride salt to afford the title compound (0.066 g, 40%) asa light yellow solid. MW=374.26. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.01 (s,1H), 10.64 (s, 1H), 8.29 (d, J=7.0 Hz, 1H), 7.97-7.95 (m, 1H), 7.81-7.77(m, 1H), 7.73-7.69 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.51 (s, 1H),7.41-7.29 (m, 5H), 7.13-7.09 (m, 1H), 6.91 (s, 1H), 3.42 (s, 2H); APCIMS m/z 338 [M+H]⁺.

EXAMPLE 84 2-(4-((2-(3-Chlorophenyl)pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure A2, 4-chloro-2-(3-chlorophenyl)pyridinehydrochloride (0.114 g, 0.44 mmol) was reacted with2-(4-aminophenyl)ethanol (0.072 g, 0.53 mmol), followed by formation ofthe hydrochloride salt to afford the title compound (0.103 g, 65%) as alight yellow solid. MW=361.27. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.08 (s,1H), 10.70 (s, 1H), 8.28 (d, J=7.0 Hz, 1H), 7.96 (t, J=2.0 Hz, 1H), 7.79(d, J=7.5 Hz, 1H), 7.73-7.69 (m, 1H), 7.65 (t, J=8.0 Hz, 1H), 7.37-7.28(m, 5H), 7.13-7.08 (m, 1H), 3.64 (t, J=7.0 Hz, 2H), 2.76 (t, J=7.0 Hz,2H); APCI MS m/z 325 [M+H]⁺.

EXAMPLE 853-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propan-1-olhydrochloride

Following general procedure A2, employing iso-propanol as the solvent,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with3-(4-aminophenyl)propan-1-ol (0.075 g, 0.50 mmol), followed by formationof the hydrochloride salt to afford the title compound (0.022 g, 16%) asan off-white solid. MW=415.36. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.00 (s,1H), 9.74 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.71-7.64 (m, 2H), 7.62-7.57(m, 1H), 7.32 (s, 4H), 6.98 (s, 1H), 3.43 (t, J=6.4 Hz, 2H), 3.15 (t,J=7.7 Hz, 2H), 2.91 (q, J=7.2 Hz, 2H), 2.67-2.63 (m, 2H), 2.24 (quin,J=7.5 Hz, 2H), 1.77-1.71 (m, 2H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 862-(3-Chlorophenyl)-N-(4-(2-methoxyethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-aminehydrochloride

Following general procedure A2 except using iso-propanol as a solvent,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.107 g, 0.35 mmol) was reacted with4-(2-methoxyethyl)aniline (0.108 g, 0.71 mmol), followed by formation ofthe hydrochloride salt to afford the title compound (0.094 g, 64%) as awhite solid. MW=415.36. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.03 (s, 1H), 9.75(s, 1H), 7.89 (t, J=1.9 Hz, 1H), 7.71-7.67 (m, 2H), 7.59 (t, J=7.9 Hz,1H), 7.36-7.32 (m, 4H), 6.99 (s, 1H), 3.57 (t, J=6.8 Hz, 2H), 3.25 (s,3H), 3.15 (t, J=7.5 Hz, 2H), 2.91 (t, J=7.2 Hz, 2H), 2.85 (t, J=6.8 Hz,2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 87 Methyl4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzoatehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with methyl4-aminobenzoate (0.055 g, 0.36 mmol), followed by formation of thehydrochloride salt to afford the title compound (0.100 g, 80%) as awhite solid. MW=415.31. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.94 (s, 1H), 8.05(d, J=8.5 Hz, 2H), 7.98-7.96 (m, 1H), 7.81-7.77 (m, 1H), 7.68-7.64 (m,1H), 7.60 (t, J=7.5 Hz, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.33 (s, 1H), 3.86(s, 3H), 3.18 (t, J=7.5 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.24 (quin,J=7.5 Hz, 2H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 88(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)methanol

To a solution of methyl4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzoate(0.075 g, 0.19 mmol) in THF (5 mL) at 0° C. was added lithium aluminumhydride (1.0 M, 0.6 mL, 0.6 mmol). The mixture warmed to rt and stirredfor 2 d. After this time, the reaction was quenched with water and NaOH(2 M), dried over anhydrous sodium sulfate, filtered, and the filtratewas concentrated. The residue was purified by column chromatography(silica, hexanes/ethyl acetate) to afford the title compound (0.049 g,71%) as an off-white solid. MW=350.84. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.15(s, 1H), 7.91-7.89 (m, 1H), 7.76-7.73 (m, 1H), 7.45-7.40 (m, 2H), 7.32(d, J=8.5 Hz, 2H), 7.23-7.19 (m, 3H), 5.11 (t, J=6.0 Hz, 1H), 4.48 (d,J=6.0 Hz, 2H), 2.91 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.08(quin, J=7.5 Hz, 2H); APCI MS m/z 351 [M+H]⁺.

EXAMPLE 89 Methyl2-(5-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-2-yl)acetatehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.110 g, 0.36 mmol) was reacted with methyl2-(5-aminopyridin-2-yl)acetate (0.067 g, 0.40 mmol), followed byformation of the hydrochloride salt to afford the title compound (0.110g, 74%) as a white solid. MW=466.79. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.31(s, 1H), 10.00 (s, 1H), 8.63 (d, J=2.5 Hz, 1H), 7.97-7.93 (m, 2H),7.78-7.75 (m, 1H), 7.69-7.66 (m, 1H), 7.61 (t, J=7.5 Hz, 1H), 7.54 (d,J=8.5 Hz, 1H), 7.12 (s, 1H), 3.95 (s, 2H), 3.65 (s, 3H), 3.19 (t, J=7.5Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H); APCI MS m/z394 [M+H]⁺.

EXAMPLE 902-(5-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-2-yl)ethanolhydrochloride

Step 1. Preparation of 2-(5-aminopyridin-2-yl)ethanol

To a solution of methyl 2-(5-aminopyridin-2-yl)acetate (0.250 g, 1.5mmol) in THF (20 mL) at 0° C. was added lithium aluminum hydride (1.0 M,3.75 mL, 3.75 mmol). The mixture was warmed to rt and stirred for 2 h.After this time, the reaction was quenched with water and NaOH (2 M),dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.046 g, 22%) asan orange oil. MW=138.17. ¹H NMR (CDCl₃, 500 MHz) δ 8.01-7.97 (m, 1H),6.97-6.92 (m, 2H), 3.96 (t, J=5.5 Hz, 2H), 3.60 (s, 2H), 2.89 (t, J=5.5Hz, 2H); APCI MS m/z 139 [M+H]⁺.

EXAMPLE 912-(5-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-2-yl)ethanolhydrochloride

Following general procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.075 g, 0.25 mmol) was reacted with2-(5-aminopyridin-2-yl)ethanol (0.045 g, 0.33 mmol), followed byformation of the hydrochloride salt to afford the desired product (0.023g, 21%) as a white solid. MW=438.78. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.38(s, 1H), 10.12 (s, 1H), 8.72 (s, 1H), 8.10 (s, 1H), 7.98-7.95 (m, 1H),7.78 (d, J=7.5 Hz, 1H), 7.71-7.58 (m, 3H), 7.21 (s, 1H), 3.80 (t, J=8.0Hz, 2H), 3.20 (t, J=8.0 Hz, 2H), 3.03 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H); APCI MS m/z 366 [M+H]⁺.

EXAMPLE 922-(6-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-3-yl)ethanolhydrochloride

Following general procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.110 g, 0.37 mmol) was reacted with2-(6-aminopyridin-3-yl)ethanol (0.100 g, 0.74 mmol), followed byformation of the hydrochloride salt to afford the title compound (0.096g, 65%) as a light yellow solid. MW=402.32. ¹H NMR (DMSO-d₆, 500 MHz) δ14.47 (s, 1H), 9.92 (s, 1H), 8.81-8.75 (m, 1H), 8.28 (s, 1H), 7.97 (m,1H), 7.82-7.63 (m, 4H), 7.40 (d, J=8.5 Hz, 1H), 3.63 (t, J=6.5 Hz, 2H),3.20 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.73 (t, J=6.5 Hz, 2H),2.30-2.21 (m, 2H); APCI MS m/z 366 [M+H]⁺.

EXAMPLE 93Trans-4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl-methanolhydrochloride

Following general procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.093 g, 0.31 mmol) was reacted withtrans-(4-aminocyclohexyl)methanol hydrochloride (0.077 g, 0.47 mmol),followed by formation of the hydrochloride salt to afford the titlecompound (0.011 g, 9%) as a light yellow solid. MW=393.35. ¹H NMR(DMSO-d₆, 500 MHz) δ 13.44 (s, 1H), 7.99-7.96 (m, 1H), 7.83 (d, J=7.5Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 7.63 (t, J=8.0 Hz, 1H), 7.55 (br s,1H), 7.10 (s, 1H), 4.45-4.43 (m, 1H), 3.84-3.80 (m, 1H), 3.28-3.23 (m,2H), 3.05 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.17 (quin, J=7.5Hz, 2H); 1.92-1.90 (m, 2H), 1.79-1.77 (m, 2H), 1.45-1.34 (m, 3H),1.16-1.10 (m, 2H); APCI MS m/z 357 [M+H]⁺.

EXAMPLE 942-(6-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-3-yl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(6-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-3-yl)acetatehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.112 g, 0.37 mmol) was reacted with ethyl2-(6-aminopyridin-3-yl)acetate (0.134 g, 0.75 mmol), followed byformation of the hydrochloride salt to afford the title compound (0.136g, 85%) as a light yellow solid. MW=444.35. ¹H NMR (DMSO-d₆, 300 MHz) δ14.47 (s, 1H), 9.92 (s, 1H), 8.83-8.76 (m, 1H), 8.35-8.29 (m, 1H),7.99-7.95 (m, 1H), 7.84-7.75 (m, 2H), 7.74-7.61 (m, 2H), 7.42 (d, J=8.5Hz, 1H), 4.10 (q, J=7.0 Hz, 2H), 3.73 (s, 2H), 3.20 (t, J=7.5 Hz, 2H),3.06 (t, J=7.5 Hz, 2H), 2.26 (quin, J=7.5 Hz, 2H), 1.20 (t, J=7.0 Hz,3H); APCI MS m/z 408 [M+H]⁺.

EXAMPLE 942-(6-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-3-yl)acetamidehydrochloride

Following general procedure C, ethyl2-(6-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)pyridin-3-yl)acetate(0.100 g, 0.24 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.100 g, 75%) as a white solid. MW=415.32. ¹H NMR (DMSO-d₆,500 MHz) δ 14.36 (s, 1H), 9.86 (s, 1H), 8.80-8.76 (m, 1H), 8.31-8.27 (m,1H), 7.98-7.95 (m, 1H), 7.82-7.78 (m, 1H), 7.77-7.74 (m, 1H), 7.72-7.63(m, 2H), 7.58-7.53 (m, 1H), 7.38 (d, J=8.5 Hz, 1H), 6.97 (s, 1H), 3.42(s, 2H), 3.19 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.26 (t, J=7.5Hz, 2H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 95Trans-2-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl)acetonitrilehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.108 g, 0.36 mmol) was reacted with2-(4-aminocyclohexyl)acetonitrile (0.120 g, 0.72 mmol), followed byformation of the hydrochloride salt to afford the title compound (0.068g, 47%) as a white solid. MW=402.36. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.51(s, 1H), 7.99-7.96 (m, 1H), 7.84 (d, J=7.5 Hz, 1H), 7.71-7.68 (m, 1H),7.64 (t, J=7.5 Hz, 1H), 7.62-7.57 (m, 2H), 7.14 (s, 1H), 3.95-3.79 (m,1H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5Hz, 2H), 1.95-1.88 (m, 2H), 1.85-1.77 (m, 2H), 1.68-1.58 (m, 1H),1.37-1.22 (m, 2H); APCI MS m/z 366 [M+H]⁺.

EXAMPLE 96Trans-2-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl)acetamidehydrochloride

Trans-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl)acetonitrilehydrochloride (0.056 g, 0.14 mmol) was suspended in sulfuric acid (2 mL)at 0° C. The reaction was warmed to rt and stirred for 16 h. After thistime, the mixture was added dropwise to a saturated NaHCO₃ solution,extracted with ethyl acetate, dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, dichloromethane/methanol), followed byformation of the hydrochloride salt to afford the title compound (0.048g, 82%) as a white solid. MW=420.38. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.50(s, 1H), 7.99-7.96 (m, 1H), 7.86-7.82 (m, 1H), 7.71-7.67 (m, 1H),7.62-7.58 (m, 2H), 7.27 (s, 1H), 7.10 (s, 1H), 6.73 (s, 1H), 3.89-3.79(m, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin,J=7.5 Hz, 2H), 1.96 (d, J=7.0 Hz, 2H), 1.92-1.85 (m, 2H), 1.78-1.71 (m,2H), 1.70-1.60 (m, 1H), 1.50-1.38 (m, 2H), 1.21-1.09 (m, 1H); APCI MSm/z 384 [M+H]⁺.

EXAMPLE 97Trans-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)cyclohexyl)ethanolhydrochloride

Following general procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.102 g, 0.34 mmol) was reacted with2-(4-aminocyclohexyl)ethanol (0.140 g, 1.0 mmol), followed by formationof the hydrochloride salt to afford the title compound (0.006 g, 4%) asa white solid. MW=407.38. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.48 (s, 1H),7.97 (s, 1H), 7.84 (d, J=8.0 Hz, 1H), 7.71-7.51 (m, 3H), 7.09 (s, 1H),4.34 (br s, 1H), 3.85-3.82 (m, 1H), 3.45 (t, J=6.0 Hz, 2H), 3.06 (t,J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H),1.91-1.85 (m, 2H), 1.78-1.73 (m, 2H), 1.46-1.32 (m, 5H), 1.16-1.05 (m,2H); APCI MS m/z 371 [M+H]⁺.

EXAMPLE 981-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-2-methylpropan-2-ol

Following general procedureB14-chloro-2(3-chorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.105 g, 0.35 mmol) was reacted with1-(4-aminophenyl)-2-methylpropan-2-ol (0.086 g, 0.53 mmol) to afford thetitle compound (0.100 g, 73%) as a white solid. MW=392.92. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.06 (s, 1H), 7.90-7.88 (m, 1H), 7.75-7.72 (m, 1H),7.46-7.39 (m, 2H), 7.23-7.14 (m, 5H), 4.28 (s, 1H), 2.90 (t, J=7.5 Hz,2H), 2.82 (t, J=7.5 Hz, 2H), 2.64 (s, 2H), 2.08 (quin, J=7.5 Hz, 2H),1.08 (s, 6H); APCI MS m/z 393 [M+H]⁺.

EXAMPLE 991-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-2-methylpropan-2-olhydrochloride

To a suspension of1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-2-methylpropan-2-ol(0.056 g, 0.14 mmol) in water (3 mL) and acetonitrile (1 mL) was added6M HCl (2 drops). The solution was lyophillized to afford the titlecompound (0.060 g, 98%) as a yellow solid. MW=429.38. ¹H NMR (DMSO-d₆,500 MHz) δ 14.11 (s, 1H), 9.84 (s, 1H), 7.89 (t, J=1.8 Hz, 1H),7.72-7.64 (m, 2H), 7.60 (t, J=7.8 Hz, 1H), 7.34-7.29 (m, 4H), 6.97 (s,1H), 3.16 (t, J=7.5 Hz, 2H), 2.93-2.89 (m, 2H), 2.69 (s, 2H), 2.24(quin, J=7.5 Hz, 2H), 1.08 (s, 6H); APCI MS m/z 393 [M+H]⁺.

EXAMPLE 100 Methyl2-(3-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetatehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.160 g, 0.53 mmol) was reacted with methyl2-(3-aminophenyl)acetate (0.130 g, 0.79 mmol), followed by formation ofthe hydrochloride salt to afford the title compound (0.190 g, 91%) as awhite solid. MW=429.34. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.04 (s, 1H), 9.81(s, 1H), 7.92 (t, J=1.8 Hz, 1H), 7.76-7.71 (m, 1H), 7.69-7.64 (m, 1H),7.60 (t, J=7.9 Hz, 1H), 7.44 (t, J=7.9 Hz, 1H), 7.38-7.34 (m, 1H),7.33-7.28 (m, 1H), 7.23-7.17 (m, 1H), 7.09 (s, 1H), 3.77 (s, 2H), 3.62(s, 3H), 3.16 (t, J=7.5 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.24 (quin,J=7.5 Hz, 2H); APCI MS m/z 393 [M+H]⁺.

EXAMPLE 1012-(3-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, methyl2-(3-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.090 g, 0.23 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.082 g, 86%) as a light yellow solid. MW=414.33. ¹H NMR(DMSO-d₆, 500 MHz) δ 14.13 (s, 1H), 9.87 (s, 1H), 7.94 (t, J=1.8 Hz,1H), 7.79-7.74 (m, 1H), 7.68-7.64 (m, 1H), 7.63-7.54 (m, 2H), 7.42 (t,J=7.8 Hz, 1H), 7.36-7.35 (m, 1H), 7.30-7.25 (m, 1H), 7.24-7.18 (m, 1H),7.09 (s, 1H), 6.92 (s, 1H), 3.45 (s, 2H), 3.17 (t, J=7.5 Hz, 2H), 2.93(t, J=7.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 378 [M+H]⁺.

EXAMPLE 1022-(3-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure E2, methyl2-(3-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.080 g, 0.20 mmol) was reacted with BH₃.DMS (2.0 M, 0.30 mL, 0.60mmol), followed by formation of the hydrochloride salt to afford thetitle compound (0.064 g, 80%) as a light yellow solid. MW=401.33. ¹H NMR(DMSO-d₆, 500 MHz) δ 14.08 (s, 1H), 9.81 (s, 1H), 7.90 (t, J=1.8 Hz,1H), 7.76-7.68 (m, 1H), 7.67-7.63 (m, 1H), 7.59 (t, J=7.8 Hz, 1H), 7.40(t, J=7.8 Hz, 1H), 7.30-7.27 (m, 1H), 7.26-7.23 (m, 1H), 7.20-7.16 (m,1H), 7.09 (s, 1H), 3.65 (t, J=6.5 Hz, 2H), 3.16 (t, J=7.5 Hz, 2H), 2.92(t, J=7.5 Hz, 2H), 2.77 (t, J=6.5 Hz, 2H), 2.24 (quin, J=7.5 Hz, 2H);APCI MS m/z 365 [M+H]⁺.

EXAMPLE 1034-((4-(2-Amino-2-oxoethyl)phenyl)amino)-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine1-oxide

To a solution of2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(0.070 g, 0.18 mmol) in chloroform (20 mL) at rt was added MCPBA (77%,0.062 g, 0.28 mmol). The mixture stirred at rt for 16 h and thenpurified by preparative HPLC (water/acetonitrile with 0.05% TFA) toafford the title compound (0.017 g, 23%) as a white solid. MW=393.87. ¹HNMR (DMSO-d₆, 500 MHz) δ 9.52 (s, 1H), 7.76-7.73 (m, 1H), 7.64-7.60 (m,1H), 7.59-7.52 (m, 2H), 7.47 (s, 1H), 7.36-7.26 (m, 4H), 6.88 (s, 1H),6.83 (s, 1H), 3.38 (s, 2H), 3.19 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz,2H), 2.25 (quin, J=7.5 Hz, 2H); APCI MS m/z 394 [M+H]⁺.

EXAMPLE 1041-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propan-2-ol

To a solution of1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propan-2-one(0.076 g, 0.20 mmol) in methanol (5 mL) was added sodium borohydride(0.015 g, 0.40 mmol). The mixture stirred at rt for 30 min. After thistime, the mixture was diluted with a saturated solution of NaHCO₃ andextracted with ethyl acetate. The organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by preparative HPLC (water/acetonitrile with 0.05% TFA) toafford the title compound (0.015 g, 20%) as a white solid. MW=378.89. ¹HNMR (DMSO-d₆, 500 MHz) δ 8.07 (s, 1H), 7.91-7.88 (m, 1H), 7.76-7.72 (m,1H), 7.46-7.39 (m, 2H), 7.22-7.15 (m, 5H), 4.53 (d, J=4.5 Hz, 1H),3.87-3.79 (m, 1H), 2.90 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H),2.71-2.65 (m, 1H), 2.58-2.53 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H), 1.05(d, J=6.0 Hz, 3H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 1052-(3-Chlorophenyl)-N-(4-(2-(dimethylamino)ethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-aminehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.083g, 0.31 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline (0.062g, 0.37 mmol), followed by formation of the hydrochloride salt to affordthe title compound (0.098 g, 67%) as a light yellow solid. MW=464.86. ¹HNMR (DMSO-d₆, 500 MHz) δ 10.16 (s, 1H), 8.33 (s, 1H), 7.91-7.89 (m, 1H),7.79-7.74 (m, 1H), 7.48-7.42 (m, 2H), 7.31-7.28 (m, 4H), 7.21 (s, 1H),3.29-3.26 (m, 2H), 3.02-2.90 (m, 4H), 2.87-2.78 (m, 8H), 2.10 (quin,J=7.5 Hz, 2H); APCI MS m/z 392 [M+H]⁺.

EXAMPLE 106(R)-1-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propan-2-ol

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.086g, 0.32 mmol) was reacted with (R)-1-(4-aminophenyl)propan-2-ol (0.058g, 0.38 mmol) to afford the title compound (0.027 g, 22%) as a lightyellow solid. MW=378.89. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.06 (s, 1H),7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m,5H), 4.53 (d, J=4.5 Hz, 1H), 3.86-3.78 (m, 1H), 2.90 (t, J=7.5 Hz, 2H),2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.08(quin, J=7.5 Hz, 2H), 1.05 (d, J=6.5 Hz, 3H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 107(S)-1-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propan-2-ol

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.089g, 0.34 mmol) was reacted with (S)-1-(4-aminophenyl)propan-2-ol (0.061g, 0.41 mmol) to afford the title compound (0.034 g, 26%) as a lightyellow solid. MW=378.89. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.06 (s, 1H),7.91-7.88 (m, 1H), 7.76-7.72 (m, 1H), 7.46-7.38 (m, 2H), 7.23-7.14 (m,5H), 4.53 (d, J=4.5 Hz, 1H), 3.86-3.78 (m, 1H), 2.90 (t, J=7.5 Hz, 2H),2.82 (t, J=7.5 Hz, 2H), 2.71-2.65 (m, 1H), 2.58-2.52 (m, 1H), 2.08(quin, J=7.5 Hz, 2H), 1.05 (d, J=6.5 Hz, 3H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 1082-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-3-hydroxypropanamidehydrochloride

Step 1. Preparation of isopropyl3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-3-oxopropanoate

Following general procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.060g, 0.23 mmol) was reacted with isopropyl3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.057 g, 0.23 mmol) to affordthe title compound (0.052 g, 47%) as a light yellow solid. MW=477.98.APCI MS m/z 478 [M+H]⁺.

EXAMPLE 108 HC Salt.2-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-3-hydroxypropanamidehydrochloride

To a solution of isopropyl3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-3-oxopropanoate(0.052 g, 0.11 mmol) in THF (5 mL) was added lithium aluminum hydride(1.0 M, 0.22 mL, 0.22 mmol). The mixture stirred at 0° C. for 3 h. Afterthis time, the mixture was quenched with water and sodium hydroxide (2M)and then extracted with ethyl acetate. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.014 g, 28%) asa yellow solid. MW=458.38. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.93 (s, 1H),9.74 (s, 1H), 7.89-7.86 (m, 1H), 7.70-7.65 (m, 2H), 7.63-7.58 (m, 1H),7.33-7.27 (m, 4H), 7.23 (s, 1H), 6.96 (s, 1H), 6.74 (s, 1H), 3.59-3.53(m, 1H), 3.15 (t, J=7.5 Hz, 2H), 2.94-2.87 (m, 2H), 2.82-2.69 (m, 2H),2.65-2.56 (m, 1H), 2.24 (quin, J=7.5 Hz, 2H); APCI MS m/z 422 [M+H]⁺.

EXAMPLE 1092-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-methylphenyl)acetonitrilehydrochloride

Following General Procedure A2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with2-(4-amino-2-methylphenyl)acetonitrile (0.073 g, 0.50 mmol), followed bythe formation of the hydrochloride salt to afford the title compound(0.063 g, 63%) as a white solid. MW=410.34. ¹H NMR (DMSO-d₆, 500 MHz) δ13.96 (s, 1H), 9.71 (s, 1H), 7.89 (t, J=1.8 Hz, 1H), 7.78-7.69 (m, 1H),7.65 (d, J=7.9 Hz, 1H), 7.59 (t, J=7.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 1H),7.30 (d, J=7.9 Hz, 1H), 7.26 (s, 1H), 7.07 (s, 1H), 4.03 (s, 2H), 3.14(t, J=7.6 Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.34 (s, 3H), 2.28-2.19 (m,2H); APCI MS m/z 374 [M+H]⁺.

EXAMPLE 1102-(3-Chlorophenyl)-N-(4-(2,2,2-trifluoroethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-aminehydrochloride

Following General Procedure A2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.075 g, 0.25 mmol) was reacted with4-(2,2,2-trifluoroethyl)aniline (0.066 g, 0.37 mmol), followed by theformation of the hydrochloride salt to afford the title compound (0.047g, 62%) as an off-white solid. MW=439.30. ¹H NMR (DMSO-d₆, 500 MHz) δ14.07 (s, 1H), 9.77 (s, 1H), 7.91 (t, J=1.8 Hz, 1H), 7.75-7.70 (m, 1H),7.66 (d, J=7.9 Hz, 1H), 7.60 (t, J=7.9 Hz, 1H), 7.46 (q, J=7.9 Hz, 4H),7.08 (s, 1H), 3.70 (q, J=11.6 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.93 (t,J=7.6 Hz, 2H), 2.29-2.19 (m, 2H); APCI MS m/z 403 [M+H]⁺.

EXAMPLE 1112-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-methylphenyl)acetamidehydrochloride

Step 1. Preparation of 2-(4-amino-2-methylphenyl)acetamide

Sulfuric acid (26 mL) was added to2-(4-amino-2-methylphenyl)acetonitrile (0.500 g, 3.42 mmol) at 0° C. Themixture was warmed to rt for 4 h, diluted with saturated aqueous sodiumbicarbonate, and extracted with ethyl acetate. The combined organiclayer was dried over anhydrous sodium sulfate and concentrated to affordthe title compound (0.252 g, 50%) as a tan solid. MW=164.20. ¹H NMR(DMSO-d₆, 500 MHz) δ 7.09 (s, 1H), 6.81 (d, J=7.9 Hz, 1H), 6.74 (s, 1H),6.39-6.35 (m, 1H), 6.33-6.29 (m, 1H), 4.78 (s, 2H), 3.19 (s, 2H), 2.10(s, 3H); APCI MS m/z 165 [M+H]⁺.

EXAMPLE 1112-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-methylphenyl)acetamidehydrochloride

Following General Procedure A2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.075 g, 0.25 mmol) was reacted with4-(2,2,2-trifluoroethyl)aniline (0.062 g, 0.38 mmol), followed by theformation of the hydrochloride salt to afford the title compound (0.018g, 24%) as a tan solid. MW=428.35. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.95 (s,1H), 9.69 (s, 1H), 7.88 (t, J=1.8 Hz, 1H), 7.71-7.65 (m, 2H), 7.60 (t,J=7.9 Hz, 1H), 7.44 (s, 1H), 7.29 (d, J=7.9 Hz, 1H), 7.22-7.16 (m, 2H),7.01 (s, 1H), 6.93 (s, 1H), 3.45 (s, 2H), 3.14 (t, J=7.6 Hz, 2H), 2.91(t, J=7.6 Hz, 2H), 2.29 (s, 3H), 2.27-2.20 (m, 2H); APCI MS m/z 392[M+H]⁺.

EXAMPLE 1122-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetate

Following General Procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100g, 0.33 mmol) was reacted with ethyl 2-(4-amino-2-fluorophenyl)acetate(0.098 g, 0.50 mmol) to afford the title compound (0.094 g, 94%).MW=424.90. ¹H NMR (CD₃OD, 300 MHz) δ 7.79-7.75 (m, 1H), 7.66-7.60 (m,1H), 7.45-7.36 (m, 2H), 7.30 (t, J=8.4 Hz, 1H), 7.20 (s, 1H), 7.11-7.05(m, 1H), 7.04-6.97 (m, 1H), 4.17 (q, J=7.1 Hz, 2H), 3.68 (s, 2H), 3.02(t, J=7.6 Hz, 2H), 2.89 (t, J=7.6 Hz, 2H), 2.30-2.13 (m, 2H), 1.26 (t,J=7.6 Hz, 3H); APCI MS m/z 425 [M+H]⁺.

EXAMPLE 1122-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetamidehydrochloride

To a microwave vessel was added ethyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetate(0.075 g, 0.18 mmol) and ammonia in methanol (7.0 M, 3 mL) and thevessel was sealed with an aluminum cap. The resulting mixture wasstirred at 100° C. for 24 h. After this time, the crude reactionsolution was cooled, concentrated, and purified by column chromatography(silica, hexanes/ethyl acetate), followed by the formation of thehydrochloride salt to afford the title compound (0.374 g, 49% yield) asan off-white solid. MW=431.32. ¹H NMR (DMSO-d₆, 300 MHz) δ 14.10 (s,1H), 9.80 (s, 1H), 7.93 (t, J=1.7 Hz, 1H), 7.77-7.71 (m, 1H), 7.71-7.60(m, 2H), 7.59-7.52 (m, 1H), 7.42 (t, J=8.6 Hz, 1H), 7.31-7.20 (m, 2H),7.14 (s, 1H), 7.02 (s, 1H), 3.48 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.94(t, J=7.6 Hz, 2H), 2.03 (quin, J=7.6 Hz, 2H); APCI MS m/z 396 [M+H]⁺.

EXAMPLE 1132-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)ethanolhydrochloride

To a solution of ethyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)-2-fluorophenyl)acetate(0.075 g, 0.18 mmol) in THF (2 mL) was added borane dimethyl sulfidecomplex solution (2.0 M in THF, 0.027 g, 0.35 mmol) at 0° C. Thereaction mixture was slowly warmed to rt and stirred overnight. Afterthis time, the mixture was quenched with 0.5 N HCl, and then basifiedwith saturated aqueous sodium bicarbonate. The mixture was extractedwith ethyl acetate and the residue purified by column chromatography(silica, dichloromethane/methanol), followed by the formation of thehydrochloride salt to afford the title compound (0.442 g, 44%) as a tansolid. MW=382.86. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.11 (s, 1H), 9.78 (s,1H), 7.92 (t, J=1.8 Hz, 1H), 7.75-7.71 (m, 1H), 7.69-7.65 (m, 1H), 7.61(t, J=7.9 Hz, 1H), 7.42 (t, J=7.9 Hz, 1H), 7.27-7.19 (m, 2H), 7.12 (s,1H), 3.63 (t, J=6.9 Hz, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz,2H), 2.78 (t, J=6.9 Hz, 2H), 2.24 (quin, J=7.6 Hz, 2H); APCI MS m/z 383[M+H]⁺.

EXAMPLE 1142-(3-Chlorophenyl)-N-(4-(oxazol-2-ylmethyl)phenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-aminehydrochloride

Following General Procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.075g, 0.25 mmol) was reacted with 4-(oxazol-2-ylmethyl)aniline (0.065 g,0.37 mmol) followed by the formation of the hydrochloride salt to affordthe title compound (0.022 g, 30%) as an off-white solid. MW=438.35. ¹HNMR (DMSO-d₆, 300 MHz) δ 14.14 (s, 1H), 9.86 (s, 1H), 8.05-8.03 (m, 1H),7.92 (t, J=1.8 Hz, 1H), 7.75-7.57 (m, 3H), 7.40 (s, 4H), 7.16 (s, 1H),7.04 (s, 1H), 4.20 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.32-2.61 (m, 2H),2.74 (t, J=7.6 Hz, 2H); APCI MS m/z 402 [M+H]⁺.

EXAMPLE 1151-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethane-1,2-diolhydrochloride

Step 1. Preparation of2-(3-chlorophenyl)-N-(4-vinylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

Following General Procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.200g, 0.75 mmol) was reacted with 4-vinylaniline (0.099 g, 0.83 mmol) toafford the title compound (0.230 g, 100%) as a tan solid. MW=346.85. ¹HNMR (CDCl₃, 500 MHz) δ 7.88-7.85 (m, 1H), 7.73-7.68 (m, 1H), 7.47-7.42(m, 2H), 7.35-7.29 (m, 2H), 7.21 (s, 1H), 7.20-7.16 (m, 2H), 6.72 (q,J=10.5 Hz, 1H), 5.78 (s, 1H), 5.74-5.70 (m, 1H), 5.24-5.22 (m, 1H), 3.09(t, J=7.6 Hz, 2H), 2.84 (t, J=7.6 Hz, 2H), 2.22 (quin, J=7.6 Hz, 2H);APCI MS m/z 347 [M+H]⁺.

EXAMPLE 1151-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethane-1,2-diolhydrochloride

To a solution of2-(3-chlorophenyl)-N-(4-vinylphenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine(0.100 g, 0.29 mmol) in acetone (10 mL) and water (5 mL) was added4-methylmorpholine N-oxide (0.189 g, 1.44 mmol), followed by potassiumosmate dehydrate (0.002 g, 0.06 mmol) and the reaction mixture wasstirred at rt overnight. After this time, the mixture was diluted withsaturated aqueous sodium bicarbonate and extracted with ethyl acetate.The combined organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate), followed by theformation of the hydrochloride salt to afford the title compound (0.033g, 32%) as a light yellow solid. MW=417.33. ¹H NMR (DMSO-d₆, 500 MHz) δ14.03 (s, 1H), 9.79 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.72-7.64 (m, 2H),7.63-7.57 (m, 1H), 7.45 (d, J=8.0 Hz, 2H), 7.36 (d, J=8.0 Hz, 2H), 7.00(s, 1H), 4.57 (t, J=6.0 Hz, 1H), 3.51-3.45 (m, 2H), 3.15 (t, J=7.6 Hz,2H), 2.92 (t, J=7.6 Hz, 2H), 2.29-2.20 (m, 2H); APCI MS m/z 381 [M+H]⁺.

EXAMPLE 1162-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propanamidehydrochloride

Step 1. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propanoate

Following General Procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150g, 0.57 mmol) was reacted with methyl 2-(4-aminophenoxy)propanoate(0.133 g, 0.68 mmol) to afford the title compound (0.146 g, 97%) as anoff-white solid. MW=422.90. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.98 (s, 1H),7.88-7.86 (m, 1H), 7.74-7.69 (m, 1H), 7.46-7.38 (m, 2H), 7.22-7.17 (m,2H), 7.02 (s, 1H), 6.96-6.89 (m, 2H), 4.96 (q, J=6.8 Hz, 1H), 3.69 (s,3H), 2.89 (t, J=7.6 Hz, 2H), 2.80 (t, J=7.6 Hz, 2H), 2.13-2.03 (m, 2H),1.51 (d, J=6.7 Hz, 3H); APCI MS m/z 423 [M+H]⁺.

EXAMPLE 1162-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propanamidehydrochloride

Following General Procedure C, methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propanoate(0.140 g, 0.33 mmol) was reacted with ammonia in methanol (7.0 M, 4 mL),followed by the formation of the hydrochloride salt to form the titlecompound (0.093 g, 67% yield) as a yellow solid. MW=444.35. ¹H NMR(DMSO-d₆, 300 MHz) δ 14.00 (s, 1H), 9.72 (s, 1H), 7.88 (t, J=1.8 Hz,1H), 7.71-7.64 (m, 2H), 7.63-7.55 (m, 2H), 7.38-7.26 (m, 3H), 7.05-6.97(m, 2H), 6.87 (s, 1H), 6.65 (q, J=6.7 Hz, 1H), 3.14 (t, J=7.6 Hz, 2H),2.99-2.81 (m, 2H), 2.31-2.14 (m, 2H) 1.46 (d, J=6.6 Hz, 3H); APCI MS m/z408 [M+H]⁺.

EXAMPLE 1172-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propan-1-olhydrochloride

To a solution of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenoxy)propanoate(0.050 g, 0.12 mmol) in dichloromethane at 0° C. was added DIBAL (0.034g, 0.24 mmol, 1.0 M in THF) over 15 min. Then, the mixture was stirredfor 1 h at 0° C. and then warmed to rt for 15 min. After this time, thereaction was quenched with methanol, HCl (2 M) and water, and thenextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate), followed by the formation of the hydrochloride salt to formthe title compound (0.033 g, 66%) as a bright yellow gum. MW=431.35. ¹HNMR (DMSO-d₆, 500 MHz) δ 13.97 (s, 1H), 9.73 (s, 1H), 7.86 (t, J=1.8 Hz,1H), 7.68-7.62 (m, 2H), 7.57 (t, J=7.9 Hz, 1H), 7.31-7.26 (m, 2H),7.06-7.01 (m, 2H), 6.86 (s, 1H), 4.49-4.39 (m, 2H), 3.61-3.41 (m, 2H),3.17-3.09 (m, 2H), 2.88 (s, 2H), 2.26-2.17 (m, 2H), 1.21 (d, J=6.2 Hz,3H); APCI MS m/z 395 [M+H]⁺.

EXAMPLE 1182-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(methyl)amino)phenyl)acetamide

A mixture of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.060 g, 0.20 mmol) and2-(4-(methylamino)phenyl)acetamide (0.066 g, 0.40 mmol) in NMP (3 mL)was microwaved for 3 h at 140° C. After this time, the mixture waspurified by silica gel chromatography followed by preparative HPLC toafford the title compound (0.012 g, 15%) as a white solid. MW=391.89. ¹HNMR (DMSO-d₆, 500 MHz) δ 14.18 (br s, 1H), 8.10 (s, 1H), 7.94 (d, J=7.5Hz, 1H), 7.70-7.66 (m, 2H), 7.55 (br s, 1H), 7.37-7.27 (m, 5H), 6.92 (brs, 1H), 3.57 (s, 3H), 3.01 (t, J=7.1 Hz, 2H), 1.96-1.85 (m, 4H); ESI MSm/z 392 [M+H]⁺.

EXAMPLE 1193-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)propanamidehydrochloride

A mixture of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.060 g, 0.20 mmol) and 3-(4-aminophenyl)propanamide(0.066 g, 0.40 mmol) in NMP (3 mL) was microwaved for 3 h at 120° C.,then at 140° C. for 2.5 h. After this time, the mixture was purified bysilica gel chromatography eluting first with ethyl acetate and hexanesfollowed by methylene chloride and methanol. The solids were furtherpurified by preparative HPLC to afford the title compound (0.042 g, 54%)as a white solid. MW=391.89. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.09 (br s,1H), 9.82 (s, 1H), 7.90-7.89 (m, 1H), 7.71-7.58 (m, 3H), 7.33-7.27 (m,5H), 6.98 (s, 1H), 6.77 (br s, 1H), 3.18-3.15 (m, 2H), 2.93-2.80 (m,4H), 2.40-2.34 (m, 2H), 2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]⁺.

EXAMPLE 1202-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-N-methylacetamidehydrochloride

A mixture of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) and2-(4-aminophenyl)-N-methylacetamide (0.164 g, 1.0 mmol) was heated for 3h at 150° C., then toluene added and the mixture continued heating foran additional 3 h. After this time, the mixture was purified by silicagel chromatography eluting with methylene chloride and methanol. Theresulting solid was further purified by reverse phase preparative HPLCand then converted to the HCl salt to afford the title compound (0.065g, 50%) as a white solid. MW=391.89. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.07(br s, 1H), 9.82 (s, 1H), 8.04-8.03 (m, 1H), 7.90-7.89 (m, 1H),7.71-7.58 (m, 3H), 7.38-7.34 (m, 4H), 7.01 (s, 1H), 3.44 (s, 2H),3.18-3.14 (m, 2H), 2.93 (t, J=7.3 Hz, 2H), 2.59 (d, J=4.6 Hz, 3H),2.27-2.21 (m, 2H); ESI MS m/z 392 [M+H]⁺.

EXAMPLE 1212-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-N,N-dimethylacetamidehydrochloride

A mixture of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) and2-(4-aminophenyl)-N,N-dimethylacetamide (0.178 g, 1.0 mmol) was heatedfor 3 h at 150° C., then toluene added and the mixture continued heatingfor an additional 7 h. After this time, the mixture was purified bysilica gel chromatography eluting with methylene chloride and methanol.The resulting solid was converted to the HCl salt to afford the titlecompound (0.048 g, 33%) as a white solid. MW=405.92. ¹H NMR (DMSO-d₆,500 MHz) δ 14.2 (br s, 1H), 9.88 (s, 1H), 7.91-7.90 (m, 1H), 7.72-7.66(m, 2H), 7.61-7.58 (m, 1H), 7.37-7.32 (m, 1H), 7.01 (s, 1H), 3.73 (s,2H), 3.17 (t, J=7.7 Hz, 2H), 3.04 (s, 3H), 2.93 (t, J=7.2 Hz, 2H), 2.84(s, 3H), 2.27-2.21 (m, 2H); ESI MS m/z 406 [M+H]⁺.

EXAMPLE 1222-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonamidehydrochloride

Step 1. Preparation of diisopropyl 2-(4-nitrobenzyl)malonate

A 250-mL round bottom flask was charged with diisopropyl malonate (2.09g, 11.1 mmol) in DMF (24 mL). Sodium hydride (60% suspension, 0.44 g,11.1 mmol) was slowly added to this solution at 0° C. After 15 minutes,a solution of 4-nitrobenzyl bromide (2.00 g, 9.26 mmol, 1.0 eq.) in DMF(24 mL) was added in one portion and then the reaction was stirred for19 h. After this time, the reaction was warmed to rt. The reaction wasquenched with 2N HCl then diluted in water (300 mL) and extracted withmethyl tert-butylether (3×50 mL). The combined extract was washed withsaturated sodium chloride (2×25 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by column chromatography on silica eluting with 9:1hexanes/ethyl acetate to afford the title compound (2.02 g, 67%) as acolorless oil. MW=323.34. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.15 (d, J=10.0Hz, 2H), 7.53 (d, J=9.0 Hz, 2H), 4.88 (septet, J=6.5 Hz, 2H), 3.89 (t,J=8.5 Hz, 1H), 3.19 (d, J=8.5 Hz, 2H), 1.14 (d, J=6.5 Hz, 6H), 1.11 (d,J=6.5 Hz, 6H).

Step 2. Preparation of 2-(4-nitrobenzyl)malonamide

A 100-mL round bottom flask was charged with diisopropyl2-(4-nitrobenzyl)malonate (2.00 g, 6.18 mmol) in methanol (10 mL). Tothis solution at rt was added 7N ammonia in methanol (8.8 mL, 61.8mmol). The reaction was stirred for 44 h then concentrated under reducedpressure. The residue was suspended in dichloromethane and the solidisolated by filtration to afford the title compound (0.40 g, 27%) as awhite solid. MW=237.21. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.14 (d, J=8.5 Hz,2H), 7.48 (d, J=8.5 Hz, 2H), 7.27 (s, 2H), 7.07 (s, 2H), 3.39 (t, J=7.5Hz, 1H), 3.10 (d, J=7.5 Hz, 2H).

Step 3. Preparation of 2-(4-aminobenzyl)malonamide

A 100-mL round bottom flask was charged with 2-(4-nitrobenzyl)malonamide(0.40 g, 1.68 mmol) and 10% palladium on carbon (0.10 g) in 1:2 ethylacetate/ethanol (15 mL). This mixture was vigorously stirred under H₂ (1atm) for 56 h. After this time, the mixture was filtered through celiteto afford the title compound (0.17 g, 49%) as a white solid. MW=207.23.¹H NMR (DMSO-d₆, 500 MHz) δ 7.16 (s, 2H), 6.95 (s, 2H), 6.82 (d, J=8.5Hz, 2H), 6.43 (d, J=8.5 Hz, 2H), 4.81 (s, 2H), 3.17 (t, J=8.0 Hz, 1H),2.78 (d, J=7.5 Hz, 2H).

EXAMPLE 1222-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonamidehydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol), 2-(4-aminobenzyl)malonamide (0.110g, 0.53 mmol) and conc. HCl (1 drop) in NMP (3 mL). The resultingmixture was heated at 140° C. under microwave irradiation for 3 h. Afterthis time, the reaction mixture was cooled, diluted with water (15 mL)and then treated with saturated sodium bicarbonate until pH ˜8. Theresulting solid was isolated by filtration and purified by preparativeHPLC (water/acetonitrile with 0.05% TFA) to afford the free base of thetitle compound (0.070 g, 56%) as an off-white solid. MW=434.92. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.07 (s, 1H), 7.90 (s, 1H), 7.75-7.70 (m, 1H),7.46-7.38 (m, 2H), 7.24 (s, 2H), 7.21-7.13 (m, 5H), 7.02 (s, 2H),4.08-4.00 (m, 1H), 2.96 (d, J=7.0 Hz, 2H), 2.93-2.87 (m, 2H), 2.85-2.78(m, 2H), 2.22-2.13 (m, 2H). MS: ESI⁺, m/z 435 [M+H]⁺. Treatment with1.25M HCl in methanol (0.19 mL, 0.24 mmol, 1.5 eq.) afforded the titlecompound (0.048 g, 64%) as an off-white solid. MW=471.38. m.p. 219-222°C. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.95 (br s, 1H), 9.71 (s, 1H), 7.90-7.87(m, 1H), 7.70-7.74 (m, 2H), 7.60 (t, J=8.0 Hz, 1H), 7.31 (s, 5H), 7.03(s, 2H), 6.97 (s, 1H), 3.36-3.33 (m, 1H), 3.13 (t, J=7.5 Hz, 2H), 3.01(d, J=7.5 Hz, 2H), 3.13 (t, J=7.0 Hz, 2H), 2.28-2.19 (m, 2H); ESI MS m/z435 [M+H]⁺.

EXAMPLE 123 Diisopropyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonatehydrochloride

Step 1. Preparation of diisopropyl 2-(4-aminobenzyl)malonate

A 100-mL round bottom flask was charged with diisopropyl2-(4-nitrobenzyl)malonate (1.19 g, 3.68 mmol) and 10% palladium oncarbon (0.30 g) in 1:1 ethyl acetate/methanol (20 mL). This mixture wasvigorously stirred under H₂ (1 atm) for 2.5 h. After this time, themixture was filtered through celite and purified by chromatography onsilica eluting with hexanes/ethyl acetate (10:1 to 0:10) to afford thetitle compound (0.34 g, 32%) as a white solid. MW=293.36. ¹H NMR(DMSO-d₆, 500 MHz) δ 6.83 (d, J=7.5 Hz, 2H), 6.44 (d, J=7.0 Hz, 2H),4.91-4.82 (m, 4H), 3.55 (t, J=8.0 Hz, 1H), 2.86 (d, J=8.0 Hz, 2H), 1.14(d, J=6.0 Hz, 6H), 1.11 (d, J=8.0 Hz, 6H).

EXAMPLE 123 Diisopropyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonatehydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.070 g, 0.23 mmol), diisopropyl2-(4-aminobenzyl)malonate (0.136 g, 0.47 mmol) and conc. HCl (1 drop) inNMP (3 mL). The resulting mixture was heated at 140° C. under microwaveirradiation for 2 h. After this time, the reaction mixture was cooled,diluted with water (15 mL), and then treated with saturated sodiumbicarbonate until pH ˜8. The resulting solid was isolated by filtrationand purified by preparative HPLC (water/acetonitrile with 0.05% TFA)followed by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as eluent to afford diisopropyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)malonate(0.046 g, 38%) as an off-white solid. MW=521.05. ¹H NMR (DMSO-d₆, 500MHz) δ 8.14 (s, 1H), 7.86 (s, 1H), 7.89-7.84 (m, 1H), 7.46-7.38 (m, 2H),7.25-7.12 (m, 5H), 4.94-4.84 (m, 2H), 3.78-3.72 (m, 1H), 3.04 (d, J=7.5Hz, 2H), 2.93-2.87 (m, 2H), 2.85-2.77 (m, 2H), 2.12-2.03 (m, 2H), 1.15(d, J=5.5 Hz, 6H), 1.11 (d, J=5.5 Hz, 6H). MS: ESI, m/z 521 [M+H]⁺.Treatment with 1.25M HCl in methanol (0.11 mL, 0.13 mmol, 1.5 eq.)afforded the title compound (0.043 g, 88%) as an off-white solid.MW=557.51. M.p. 68-70° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.93 (br s, 1H),7.86-7.84 (m, 1H), 7.67 (d, J=8.0 Hz, 1H), 7.62-7.50 (m, 2H), 7.34-7.24(m, 4H), 6.97 (s, 1H), 4.88 (sept, J=6.0 Hz, 2H), 3.79 (t, J=7.5 Hz,1H), 3.12-3.03 (m, 4H), 2.87 (t, J=7.5 Hz, 2H), 2.23-2.15 (m, 2H), 1.14(d, J=5.0 Hz, 6H), 1.09 (d, J=5.5 Hz, 6H); ESI MS m/z 451 [M+H]⁺.

EXAMPLE 1242-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-2-methylmalonamidehydrochloride

Step 1. Preparation of diisopropyl 2-methyl-2-(4-nitrobenzyl)malonate

A 250-mL round bottom flask was charged with diisopropyl2-(4-nitrobenzyl)malonate (1.61 g, 4.98 mmol) in DMF (24 mL). To thissolution at 0° C. was slowly added NaH (60% suspension, 0.24 g, 5.97mmol). After 30 minutes, iodomethane (0.37 mL, 5.97 mmol) was added inone portion. The reaction was stirred for 21 h, at which time, thereaction was warmed to rt. The reaction was diluted in water (250 mL)and extracted with methyl tert-butylether (3×75 mL). The combinedextract was washed with saturated sodium chloride (2×20 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by chromatography on silica using hexanes/ethylacetate (10:0 to 8:2) as eluent to afford the title compound (1.44 g,86%) as a white solid. MW=337.37. ¹H NMR (CDCl₃, 300 MHz) δ 8.16-8.09(m, 2H), 7.37-7.30 (m, 2H), 5.05 (sept, J=6.3 Hz, 2H), 3.30 (s, 2H),1.33 (s, 3H), 1.27-1.20 (m, 12H).

Step 2. Preparation of 2-methyl-2-(4-nitrobenzyl)malonic acid

An 250-mL round bottom flask was charged with diisopropyl2-methyl-2-(4-nitrobenzyl)malonate (1.15 g, 3.55 mmol), dioxane (20 ml)and water (10 ml). To this solution was then added lithium hydroxidemonohydrate (0.74 g, 17.8 mmol). The resulting mixture was stirred at50° C. for 22 h. After this time, the reaction mixture was cooled andacidified with 2N aqueous HCl (10 mL). The mixture was diluted withethyl acetate (100 mL) and the organic layer washed with saturatedsodium chloride (2×10 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford the title compound (0.96g, 100%) as a white solid. MW=253.21. ¹H NMR (DMSO-d₆, 300 MHz) δ 13.04(br s, 2H), 8.20-8.12 (m, 2H), 7.49-7.42 (m, 2H), 3.21 (s, 2H), 1.17 (s,3H).

Step 3. Preparation of 2-methyl-2-(4-nitrobenzyl)malonamide

An 250-mL round bottom flask was charged with2-methyl-2-(4-nitrobenzyl)malonic acid (0.96 g, 3.55 mmol), dioxane (20ml) and dichloromethane (20 ml). To this solution at 0° C. was addedoxalyl chloride (3.0 mL, 35.5 mmol) followed by DMF (2 drops). Afterstirring for 4 h, the volatile material was removed under reducedpressure. The residue was dissolved in dichloromethane (24 mL), cooledto 0° C., then 7N ammonia in methanol (50 mL, 350 mmol) was added. Afterstirring for 15 h, the reaction mixture was concentrated under reducedpressure. The residue was suspended in water (100 mL) affording a solid.The solid was isolated by filtration to afford the title compound (0.69g, 78%) as an off-white solid. MW=251.24. ¹H NMR (DMSO-d₆, 300 MHz) δ8.13 (d, J=8.7 Hz, 2H), 7.45 (d, J=8.7 Hz, 2H), 7.24 (d, J=11.4 Hz, 4H),3.22 (s, 2H), 1.14 (s, 3H).

Step 4. Preparation of 2-(4-aminobenzyl)-2-methylmalonamide

A 250-mL round bottom flask was charged with2-methyl-2-(4-nitrobenzyl)malonamide (0.69 g, 2.74 mmol) and 10%palladium on carbon (0.17 g) in 1:2 ethyl acetate/ethanol (30 mL). Thismixture was vigorously stirred under H₂ (1 atm) for 6 h. The mixture wasthen filtered through celite to afford the title compound (0.28 g, 46%)as an off-white solid. MW=221.26. ¹H NMR (DMSO-d₆, 300 MHz) δ 7.15 (s,2H), 7.08 (s, 2H), 6.80 (d, J=8.1 Hz, 2H), 6.41 (d, J=8.1 Hz, 2H), 4.87(s, 2H), 2.86 (s, 2H), 1.07 (s, 3H).

EXAMPLE 1242-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-2-methylmalonamidehydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100g, 0.38 mmol), 2-(4-aminobenzyl)-2-methylmalonamide (0.167 g, 0.75 mmol)and 4M HCl in dioxane (0.095 mL, 0.38 mmol) in NMP (4 mL). The resultingmixture was heated at 150° C. under microwave irradiation for 8 h. Afterthis time, the reaction mixture was cooled, diluted with water (20 mL)and saturated aqueous sodium bicarbonate (20 mL) affording a solid. Thesolid was isolated by filtration and chromatography on silica usingdichloromethane/methanol (10:0 to 9:1) as eluent to afford2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)benzyl)-2-methylmalonamide(0.12 g, 72%) as an off-white solid. MW=448.94. ¹H NMR (DMSO-d₆, 300MHz) δ 8.10 (s, 1H), 7.92-7.89 (m, 1H), 7.74 (dt, J=6.6, 2.1 Hz, 1H),7.48-7.39 (m, 2H), 7.23 (s, 2H), 7.20-7.10 (m, 7H), 3.05 (s, 2H), 2.91(t, J=7.8 Hz, 2H), 2.81 (t, J=7.2 Hz, 2H), 2.08 (quin, J=7.2 Hz, 2H),1.14 (s, 3H). Treatment with 1.25M HCl in methanol (0.44 mL, 0.55 mmol)afforded the title compound (0.11 g, 84%) as an off-white solid.MW=485.41. M.p. 162-165° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.01 (br s,1H), 9.17 (s, 1H), 7.89 (t, J=2.0 Hz, 1H), 7.00 (dt, J=4.5, 1.5 Hz, 1H),7.60-7.52 (m, 2H), 7.28-7.20 (m, 6H), 7.15 (s, 2H), 7.05 (s, 1H), 3.10(s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.87 (d, J=7.5 Hz, 2H), 2.18 (quin,J=7.5 Hz, 2H), 1.15 (s, 3H); APCI MS m/z 449 [M+H]⁺.

EXAMPLE 1252-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamidehydrochloride

Step 1. Preparation of2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)aceticacid

A 10-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.096 g, 0.33 mmol), Pd(dppf)Cl₂ (0.027 g, 0.033 mmol), and powderedNa₂CO₃ (0.141 g, 1.33 mmol). Dioxane (3 mL) and water (1.5 mL) wereadded. The resulting mixture was stirred under Ar at 90° C. for 3 d.until the starting chloride was consumed. After cooling to roomtemperature, the reaction mixture was adsorbed onto silica (4 g).Purification by chromatography on silica using dichloromethane/methanol(10:0 to 8:2) as eluent afforded the title compound (0.067 g, 53%) as alight brown solid. MW=377.86. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.24 (br s,1H), 8.09-8.07 (m, 1H), 8.00-7.97 (m, 1H), 7.70 (s, 1H), 7.51-7.42 (m,2H), 7.25-7.16 (m, 2H), 7.15-7.09 (m, 2H), 3.97 (s, 2H), 3.51 (s, 2H),2.94 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.09-2.01 (m, 2H); ESIMS m/z 378 [M+H]⁺.

Step 2. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate

A 25-mL flask, with stirrer bar, was charged with2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)aceticacid (0.066 g, 0.17 mol), 4M HCl/methanol (0.22 mL, 0.87 mmol) andmethanol (4 mL). After 23 h, the reaction was concentrated under reducedpressure. The residue was dissolved in ethyl acetate and saturatedsodium bicarbonate (20 mL). The organic layer was washed with saturatedsodium chloride (10 mL) then dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) aseluent to afford the title compound (0.036 g, 48%) as an off-whitesolid. MW=391.89. ¹H NMR (CDCl₃, 500 MHz) δ 7.94-7.91 (m, 1H), 7.77 (dt,J=7.0, 2.0 Hz, 1H), 7.36-7.30 (m, 2H), 7.24 (s, 1H), 7.21 (d, J=8.0 Hz,2H), 7.13 (d, J=8.0 Hz, 2H), 3.95 (s, 2H), 3.69 (s, 3H), 3.60 (s, 2H),3.08 (t, J=8.0 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.18-2.09 (m, 2H); APCIMS m/z 392 [M+H]⁺.

EXAMPLE 1252-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamidehydrochloride

A 10-mL vial was charged with methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate(0.036 g, 0.09 mmol) and ammonium chloride (0.015 g, 0.27 mmol). To thiswas added methanol (2 mL) followed by NH₃ (4 mL, 7N in methanol, 27.6mmol). The vial was sealed and the resulting mixture was stirred at 100°C. for 48 hr. After this time, the crude reaction solution concentratedunder reduced pressure. The residue was adsorbed onto silica thenpurified by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as eluent to afford2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamide(0.026 g, 79%) as a white solid. MW=376.88. ¹H NMR (CDCl₃, 500 MHz) δ7.93-7.89 (m, 1H), 7.81-7.74 (m, 1H), 7.39-7.30 (m, 2H), 7.26-7.14 (m,5H), 5.55-5.25 (m, 2H), 3.97 (s, 2H), 3.56 (s, 2H), 3.08 (t, J=8.0 Hz,2H), 2.87 (t, J=7.5 Hz, 2H), 2.14 (quin, J=7.5 Hz, 2H). MS: APCI+, m/z377 [M+H]⁺. Treatment of2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamidewith 1.25M HCl in methanol afforded the title compound (0.037 g, 99%) asa white solid. MW=413.34. M.p. 178-180° C. ¹H NMR (DMSO-d₆, 500 MHz) δ8.11-8.07 (m, 1H), 8.00-7.93 (m, 1H), 7.81 (s, 1H), 7.57-7.47 (m, 2H),7.43 (br s, 1H), 7.25-7.34 (m, 4H), 6.84 (br s, 1H), 4.60 (br s, 1H),4.00 (s, 2H), 3.31 (s, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz,2H), 2.07 (quin, J=7.5 Hz, 2H); APCI MS m/z 377 [M+H]⁺.

EXAMPLE 1262-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoicacid hydrochloride

Step 1. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoate

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300g, 1.13 mmol), methyl2-methyl-2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)propanoate(0.361 g, 1.13 mmol), Pd(dppf)Cl₂ (0.093 g, 0.11 mmol), and powderedNa₂CO₃ (0.361 g, 3.41 mmol). Dioxane (8 mL) and water (4 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 2 d. Aftercooling to room temperature, the reaction mixture was filtered throughcelite washing the solids with ethyl acetate. The filtrate layers wereseparated and the organic layer was washed with saturated sodiumchloride (3×10 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 3:1) aseluent to afford the title compound (0.201 g, 42%) as a colorless oil.MW=419.94. ¹H NMR (CDCl₃, 500 MHz) δ 7.93-7.90 (m, 1H), 7.79-7.76 (m,1H), 7.37-7.31 (m, 2H), 7.28-7.23 (m, 3H), 7.10-7.14 (m, 2H), 3.94 (s,2H), 3.64 (s, 3H), 3.08 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.14(quin, J=7.5 Hz, 2H), 1.56 (s, 6H); ESI MS m/z 420 [M+H]⁺.

EXAMPLE 1262-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoicacid hydrochloride

An 250-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoate(0.200 g, 0.47 mmol), dioxane (15 ml) and water (10 ml). To thissolution was then added lithium hydroxide monohydrate (0.060 g, 1.43mmol). The resulting mixture was stirred at 50° C. for 6.5 h. The cooledreaction mixture was treated with 2N aqueous HC until pH ˜5. Thevolatile materials were removed under reduced pressure to afford impure2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoicacid hydrochloride (0.44 g, >100%). A sample (0.112 g) was purified bypreparative HPLC (water/acetonitrile with 0.05% TFA) and converted intoHCl salt to afford the title compound (0.035 g, 16%) as a white solid.MW=432.38. M.p. 182-184° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.23 (br s,1H), 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.88 (br s, 1H), 7.58-7.53(m, 2H), 7.29-7.24 (m, 4H), 4.04 (s, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.91(t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.43 (s, 6H); APCI MS m/z406 [M+H]⁺.

EXAMPLE 1272-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanamidehydrochloride

An 250-mL round bottom flask was charged with2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoicacid (0.33 g, ˜0.40 mmol) in dichloromethane (10 ml). To this mixture at0° C. was added oxalyl chloride (0.17 mL, 2.00 mmol) followed by DMF (1drop). After stirring for 3 h, the volatile material was removed underreduced pressure to afford crude acid chloride. The residue wasdissolved in dichloromethane (20 mL), cooled to 0° C. and 7N ammonia inmethanol (14.0 mL, 98 mmol) was added. After stirring for 1.25 h thevolatile material was removed under reduced pressure. The residue wasabsorbed onto silica (5 g). Purification by chromatography on silicausing hexanes/ethyl acetate as eluent afforded2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanamide(0.128 g, 79%) as a white solid. MW=404.93. ¹H NMR (CDCl₃, 500 MHz) δ7.92-7.90 (m, 1H), 7.80-7.77 (m, 1H), 7.37-7.31 (m, 4H), 7.24 (s, 1H),7.16 (d, J=8.5 Hz, 2H), 5.32 (br s, 1H), 5.16 (br s, 1H), 3.96 (s, 2H),3.09 (t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz,2H), 1.57 (s, 6H). Treatment with 1.25M HCl in methanol (0.72 mL, 0.90mmol) afforded the title compound (0.124 g, 94%) as a white solid.MW=441.39. M.p. 180-182° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.10-8.07 (m,1H), 7.99-7.94 (m, 1H), 7.88 (br s, 1H), 7.58-7.52 (m, 2H), 7.29-7.22(m, 4H), 6.83 (s, 2H), 5.50 (br s, 1H), 4.03 (s, 2H), 3.06 (t, J=7.5 Hz,2H), 2.92 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.39 (s, 6H);APCI MS m/z 405 [M+H]⁺.

EXAMPLE 1282-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropan-1-olhydrochloride

A 25-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropanoate(0.144 g, 0.31 mmol) and THF (5 mL) at rt. Borane-dimethylsulfidecomplex (0.090 mL, 0.95 mmol) was added and the resulting solution wasstirred at 55° C. for 2 h. LCMS analysis indicated only partialreduction. Borane-dimethylsulfide complex (0.100 mL, 1.05 mmol) wasadded and the resulting solution was stirred at 55° C. for a further 20h until the starting material was consumed (monitored by LCMS analysis).The reaction was quenched with methanol then treated with 2N aqueous HCl(0.1 mL) and concentrated under reduced pressure. The residue wasdiluted with methanol and then concentrated under reduced pressure. Theresidue absorbed onto silica (2 g) then purified by columnchromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) asthe eluent to afford2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)-2-methylpropan-1-ol(0.126 g, 100%) as a colorless oil. MW=391.93. ¹H NMR (CDCl₃, 500 MHz) δ7.93-7.91 (m, 1H), 7.79-7.76 (m, 1H), 7.37-7.30 (m, 4H), 7.26 (s, 1H),7.15 (d, J=8.0 Hz, 2H), 3.95 (s, 2H), 3.60 (d, J=8.0 Hz, 2H), 3.08 (t,J=8.0 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.14 (quin, J=7.5 Hz, 3H), 1.32(s, 6H), 1.18 (t, J=8.0 Hz, 1H). MS: ESI⁺, m/z 392 [M+H]⁺. Treatmentwith 1.25M HCl in methanol (0.52 mL, 2.0 eq.) afforded the titlecompound (0.121 g, 89%) as a white solid. MW=428.39. M.p. 95-97° C. ¹HNMR (DMSO-d₆, 500 MHz) δ 8.10-8.07 (m, 1H), 7.99-7.94 (m, 1H), 7.86 (brs, 1H), 7.58-7.52 (m, 2H), 7.31-7.27 (m, 2H), 7.23-7.19 (m, 2H), 4.01(s, 2H), 3.37 (s, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.92 (t, J=7.5 Hz, 2H),2.11 (quin, J=7.5 Hz, 2H), 1.17 (s, 6H); APCI MS m/z 392 [M+H]⁺.

EXAMPLE 1291-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-1-methylureahydrochloride

Step 1. Preparation of 1-methyl-1-(4-nitrophenyl)urea

A 250-mL round bottom flask was charged with N-methyl-4-nitroaniline(1.94 g, 12.7 mmol) in tetrahydrofuran (50 mL). To this stirred solutionat rt was added acetic acid (14.6 mL, 255 mmol) and sodium cyanate (8.29g, 127.5 mmol). After 24 h, the reaction mixture was concentrated underreduced pressure. The residue was suspended in water (100 mL) and theresultant solid was isolated by filtration, washing sequentially withdichloromethane and ethyl acetate to afford the title compound (0.63 g,25%) as a yellow solid. MW=195.18. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.19-8.14(m, 2H), 7.58-7.54 (m, 2H), 6.54 (br s, 2H), 3.27 (s, 3H).

Step 2. Preparation of 1-(4-aminophenyl)-1-methylurea

A 100-mL round bottom flask was charged with1-methyl-1-(4-nitrophenyl)urea (0.63 g, 3.26 mmol) and 10% palladium oncarbon (0.15 g) in 1:1 ethyl acetate/methanol (20 mL). This mixture wasvigorously stirred under H₂ (1 atm) for 5 h. After this time, themixture was filtered through celite to afford the title compound (0.54g, 100%) as a white solid. MW=165.19. ¹H NMR (DMSO-d₆, 500 MHz) δ6.90-6.86 (m, 2H), 6.57-6.53 (m, 2H), 5.29 (br s, 2H), 5.11 (s, 2H),3.00 (s, 3H).

Step 3. Preparation ofN¹-(2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-N⁴-methylbenzene-1,4-diamine

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.200 g, 0.67 mmol), 1-(4-aminophenyl)-1-methylurea(0.220 g, 1.33 mmol) and conc. HCl (2 drops) in NMP (5 mL). Theresulting mixture was heated at 140° C. under microwave irradiation for3 h. After this time, the reaction mixture was cooled, diluted withwater (40 mL) and then saturated sodium bicarbonate was added until pH˜8. The resulting solid was isolated by filtration then purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) aseluent to afford the title compound (0.071 g, 30%) as a colorless oil.MW=349.86. ¹H NMR (CDCl₃, 500 MHz) δ 7.83-7.80 (m, 1H), 7.68-7.63 (m,1H), 7.28-7.26 (m, 2H), 7.10-7.06 (m, 2H), 6.85 (s, 1H), 6.67-6.62 (m,2H), 5.55 (s, 1H), 3.76 (br s, 1H), 3.06 (t, J=7.5 Hz, 2H), 2.87 (s,3H), 2.81 (t, J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); ESI MS m/z 350[M+H]⁺.

EXAMPLE 1291-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-1-methylureahydrochloride

A 25-mL round bottom flask was charged withN^(l)-(2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)-N⁴-methylbenzene-1,4-diamine(0.100 g, 0.28 mmol) in tetrahydrofuran (1 mL). To this stirred solutionat rt was added acetic acid (0.33 mL, 5.72 mmol) and sodium cyanate(0.186 g, 2.86 mmol). After 16 h, the reaction mixture was diluted withwater (20 mL) and saturated sodium bicarbonate was added until pH ˜8, atwhich time, a solid formed. The resultant solid was isolated byfiltration, and was purified by chromatography on silica usingdichloromethane/methanol (10:0 to 19:1) as eluent to afford1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)-1-methylurea(0.090 g, 80%) as a white solid. MW=392.88. ¹H NMR (DMSO-d₆, 500 MHz) δ8.18 (s, 1H), 7.95 (t, J=2.0 Hz, 1H), 7.80 (dt, J=7.5, 1.5 Hz, 1H),7.46-7.39 (m, 2H), 7.31 (s, 1H), 7.25 (s, 4H), 5.73 (s, 2H), 2.92 (t,J=7.5 Hz, 2H), 3.13 (s, 3H), 2.85 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5Hz, 2H). MS: ESI⁺, m/z 393 [M+H]⁺. Treatment with 1.25M HCl in methanol(0.15 mL, 0.19 mmol) afforded the title compound (0.048 g, 90%) as alight yellow solid. MW=429.34. M.p. 154-157° C. decomp. ¹H NMR (DMSO-d₆,500 MHz) δ 13.93 (br s, 1H), 9.19 (br s, 1H), 7.92-7.89 (m, 1H),7.76-7.71 (m, 1H), 7.60-7.52 (m, 2H), 7.33 (s, 4H), 7.18 (s, 1H), 5.87(s, 2H), 3.16 (s, 3H), 3.07 (t, J=7.0 Hz, 2H), 2.90 (t, J=7.5 Hz, 2H),2.19 (quin, J=7.5 Hz, 2H); ESI MS m/z 393 [M+H]⁺.

EXAMPLE 1304-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)butanamidehydrochloride

Step 1. Preparation of methyl 4-(4-aminophenyl)butanoate

A 250-mL round bottom flask was charged with 4-(4-aminophenyl)butyricacid (2.00 g, 11.2 mmol) in methanol (50 mL) and treated with conc.sulfuric acid (1 mL). The resultant mixture was heated to reflux for 1.5h. After this time, methanol (˜25 mL) was distilled off. The reactionwas cooled to 60° C. and methyl tert-butyl ether was added. The mixturewas allowed to slowly cool to room temperature, then diluted withhexanes (50 mL) to afford a white solid. The solid was dissolved in THF(6 mL)/water (4 mL) and treated with conc. NH₄OH (6 mL). The mixture wasdiluted with dichloromethane (50 mL) and the layers separated. Theorganic layer was washed with saturated sodium chloride (5 mL), driedover sodium sulfate, filtered and concentrated under reduced pressure toafford the title compound (2.07 g, 96%) as a brown solid. MW=193.24. ¹HNMR (DMSO-d₆, 500 MHz) δ 6.83-6.79 (m, 2H), 6.50-6.46 (m, 2H), 4.81 (s,2H), 3.57 (s, 3H), 2.39 (t, J=7.5 Hz, 2H), 2.25 (t, J=7.5 Hz, 2H), 1.73(quin, J=7.5 Hz, 2H).

Step 2. Preparation of 4-(4-aminophenyl)butanamide

A 100-mL vial was charged with methyl 4-(4-aminophenyl)butanoate (2.07g, 10.7 mmol), ammonium chloride (0.76 g, 14.2 mmol) in methanol (10 m).To this mixture was added NH₃ (10 mL, 7N in methanol, 70.0 mmol, 6.5eq.). The vial was sealed and the resulting mixture was stirred at 100°C. for 20 h. After this time, the crude reaction solution wasconcentrated under reduced pressure. The residue was absorbed on silica(10 g) then purified by chromatography on silica usingdichloromethane/methanol (10:0 to 9:1) as eluent to afford the titlecompound (0.67 g, 35%) as a white solid. MW=178.23. ¹H NMR (DMSO-d₆, 500MHz) δ 7.20 (br s, 1H), 6.83-6.80 (m, 2H), 6.66 (br s, 1H), 6.49-6.46(m, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.01 (t, J=7.5 Hz, 2H), 1.68 (quin,J=7.5 Hz, 2H).

EXAMPLE 1304-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)butanamidehydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol), 4-(4-aminophenyl)butanamide (0.071g, 0.40 mmol) and conc. HCl (2 drops) in NMP (3 mL). The resultingmixture was heated at 120° C. under microwave irradiation for 2 h. Thereaction mixture was cooled, diluted with water (5 mL) then treated with2M aqueous sodium hydroxide until pH ˜8 affording a solid. The solid wasisolated by filtration and purified by chromatography on silica usingdichloromethane/methanol (10:0 to 19:1) as eluent followed bychromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) aseluent to afford4-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)butanamide(0.050 g, 37%) as a white solid. MW=405.92. ¹H NMR (DMSO-d₆, 500 MHz) δ8.07 (s, 1H), 7.91 (t, J=2.0 Hz, 1H), 7.74 (dt, J=7.5, 1.5 Hz, 1H),7.46-7.38 (m, 2H), 7.25 (br s, 1H), 7.22-7.15 (m, 5H), 6.71 (br s, 1H),2.91 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.55 (t, J=7.5 Hz, 2H),2.08 (quin, J=7.5 Hz, 4H), 1.79 (quin, J=7.5 Hz, 2H); ESI MS m/z 406[M+H]⁺. Treatment with 1.25M HCl in methanol afforded the title compound(0.053 g, 99%) as an off-white solid. MW=442.38. M.p. 108-111° C. ¹H NMR(DMSO-d₆, 500 MHz) δ 11.91 (br s, 1H), 8.84 (br s, 1H), 7.91-7.88 (m,1H), 7.74-7.69 (m, 1H), 7.54-7.47 (m, 2H), 7.27-7.22 (m, 5H), 7.11 (brs, 1H), 6.72 (br s, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.86 (t, J=7.5 Hz, 2H),2.57 (t, J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H), 2.09 (t, J=7.5 Hz,2H), 1.80 (quin, J=7.5 Hz, 2H); ESI MS m/z 406 [M+H]⁺.

EXAMPLE 1312-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamidehydrochloride

Step 1. Preparation of methyl2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.103g, 0.43 mol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.126 g, 0.43 mmol), Pd(dppf)Cl₂ (0.035 g, 0.043 mmol), and powderedNa₂CO₃ (0.184 g, 1.74 mmol). Dioxane (4 mL) and water (2 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 24 h. until thestarting chloride was consumed. After this time, the mixture was cooledto room temperature and the reaction mixture absorbed onto silica (4 g).Purification by chromatography on silica using dichloromethane/methanol(10:0 to 8:2) as eluent to afford2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)aceticacid. MW=351.44. MS: ESI⁺, m/z 352 [M+H]⁺. This product was dissolved inmethanol and treated with 4M HCl/methanol and stirred for 3 days. Thereaction was concentrated under reduced pressure. The residue (0.154 g)was treated with minimum saturated sodium bicarbonate then purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) aseluent to afford the title compound (0.038 g, 24%) as a colorless oil.MW=365.47. ¹H NMR (CDCl₃, 300 MHz) δ 7.23-7.17 (m, 2H), 7.14-7.08 (m,2H), 6.22 (s, 1H), 5.35-5.26 (m, 1H), 3.81 (s, 2H), 3.69 (s, 3H), 3.60(s, 2H), 2.89 (t, J=8.0 Hz, 2H), 2.72 (t, J=7.5 Hz, 2H), 2.06 (quin,J=7.5 Hz, 2H), 1.98-1.88 (m, 2H), 1.85-1.68 (m, 4H), 1.66-1.53 (m, 2H);APCI MS 366 [M+H]⁺.

EXAMPLE 1312-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetamidehydrochloride

A 20-mL vial was charged with methyl2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)methyl)phenyl)acetate(0.038 g, 0.10 mmol) and ammonium chloride (0.017 g, 0.31 mmol). To thiswas added methanol (3 mL) followed by NH₃ (4.0 mL, 7N in methanol, 28mmol). The vial was sealed and the resulting mixture was stirred at 100°C. for 42 hr. The crude reaction solution concentrated under reducedpressure. The residue was adsorbed onto silica then purified bychromatography on silica using dichloromethane/methanol (10:0 to 1:1) aseluent, followed by preparative HPLC (water/acetonitrile with 0.05%TFA), to afford the title compound (0.019 g, 54%) as a yellow solid.MW=386.91. M.p. 78-80° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.43 (br s, 1H),7.18 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 6.83 (br s, 1H), 6.51(br s, 1H), 5.31-5.25 (m, 1H), 3.86 (s, 2H), 3.32 (s, 2H), 2.84 (t,J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.02 (quin, J=7.5 Hz, 2H),1.96-1.86 (m, 2H), 1.73-1.63 (m, 4H), 1.62-1.53 (m, 2H); APCI MS m/z 351[M+H]⁺.

EXAMPLE 1322-(4-((2-(1H-Pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Step 1. Preparation of tert-butyl2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylateand 4-chloro-2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

A 20-mL sealed tube was charged with2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.250 g, 1.33 mmol),1-Boc-pyrrole-2-boronic acid (0.308 g, 1.46 mmol),tetrakis(triphenylphosphine)palladium(0) (0.076 g, 0.066 mmol), andCs₂CO₃ (1.30 g, 3.99 mmol). Toluene (8 ml), EtOH (2 ml) and water (4 ml)were added. The resulting mixture was stirred under Ar at 90° C. for 23h. After cooling to room temperature, the reaction solution was dilutedwith water (5 mL) and ethyl acetate (60 mL). The aqueous layer wasseparated and the organic layer was washed with saturated sodiumchloride (5 mL) then dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica using hexane/ethyl acetate (100:0 to 75:250) aseluent to afford tert-butyl2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate(0.138 g, 32%) as a yellow oil. MW=318.80. ¹H NMR (CDCl₃, 500 MHz) δ7.33 (dd, J=3.5, 2.0 Hz, 1H), 7.17 (s, 1H), 6.37 (dd, J=3.0, 2.0 Hz,1H), 6.21 (t, J=3.5 Hz, 1H), 3.09 (t, J=7.5 Hz, 2H), 3.04 (t, J=7.5 Hz,2H), 2.17 (quin, J=7.5 Hz, 2H), 1.38 (s, 9H). MS: ESI⁺, m/z 319 [M+H]⁺and 4-chloro-2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.077 g, 26%) as an off-white solid. MW=218.68. ¹H NMR (CDCl₃, 500 MHz)δ 9.63 (br s, 1H), 7.30 (s, 1H), 6.87-6.85 (m, 1H), 6.65-6.62 (m, 1H),6.29-6.25 (m, 1H), 3.01 (t, J=7.5 Hz, 2H), 2.96 (t, J=7.5 Hz, 2H), 2.13(quin, J=7.5 Hz, 2H); ESI MS m/z 218 [M]⁺.

EXAMPLE 1322-(4-((2-(1H-Pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.077g, 0.35 mmol), 4-aminophenethyl alcohol (0.072 g, 0.53 mmol) and conc.HCl (1 drop) in NMP (2.5 mL). The resulting mixture was heated at 140°C. under microwave irradiation for 1.5 h. After this time, the reactionmixture was cooled, diluted with saturated aqueous sodium bicarbonate(15 mL) affording a brown solid. The solid was isolated by filtrationand chromatography on silica using dichloromethane/(90:10:0.25dichloromethane/methanol. conc. NH₄OH) (10:0 to 0:10) as eluent followedby preparative HPLC (water/acetonitrile with 0.05% TFA) to afford2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol(0.039 g, 35%) as a light brown. MW=319.40. ¹H NMR (DMSO-d₆, 500 MHz) δ11.16 (br s, 1H), 7.90 (br s, 1H), 7.22-7.18 (m, 2H), 7.15-7.11 (m, 2H),7.01 (s, 1H), 6.73 (s, 1H), 6.38 (s, 1H), 6.06-6.01 (m, 1H), 4.62 (t,J=5.0 Hz, 1H), 3.65-3.58 (m, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5Hz, 2H), 2.71 (t, J=7.0 Hz, 2H), 2.05 (quin, J=7.5 Hz, 2H); ESI MS m/z320 [M+H]⁺. Treatment with 1.25 M HCl in methanol (0.25 mL, 0.32 mmol)afforded the title compound (0.034 g, 92%) as a light brown solid.MW=355.86. M.p. 138-140° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.50 (br s,1H), 12.08 (br s, 1H), 9.44 (br s, 1H), 7.36-7.32 (m, 2H), 7.30-7.26 (m,2H), 7.12-7.09 (m, 1H), 7.06 (s, 2H), 6.28-6.25 (m, 1H), 4.68 (br s,1H), 3.66 (t, J=7.0 Hz, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz,2H), 2.78 (t, J=7.0 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H); ESI MS: ES m/z320 [M+H]⁺.

EXAMPLE 1332-(4-((2-(1H-Pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of tert-butyl2-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylateand ethyl2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

A 10-mL microwave vial was charged with tert-butyl2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate(0.138 g, 0.43 mmol), 4-aminophenyl acetic acid ethyl ester (0.093 g,0.52 mmol), palladium acetate (0.005 g, 0.021 mmol), rac-BINAP (0.020 g,0.032 mmol) and cesium carbonate (0.353 g, 1.08 mmol) in dioxane (4 mL)under argon. The reaction mixture was heated to 120° C. under microwaveirradiation for 2 h. After this time, the reaction mixture was cooled,diluted with ethyl acetate (50 mL) then filtered through celite. Thefiltrate was washed with saturated sodium chloride (10 mL), dried overanhydrous sodium sulfate, filtered and the filtrate was concentratedunder reduced pressure. The residue was purified by chromatography onsilica using dichloromethane/methanol (10:0 to 9:1) to afford an ˜4:1mixture of tert-butyl2-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylateas a brown oil (0.110 g, 55%). MW=461.55 ¹H NMR (CDCl₃, 500 MHz) δ7.30-7.22 (m, 3H), 7.16-7.13 (m, 2H), 6.93 (s, 1H), 6.30 (dd, J=3.0, 1.5Hz, 1H), 6.16 (t, J=3.5 Hz, 1H), 5.67 (s, 1H), 4.15 (q, J=7.5 Hz, 2H),3.58 (s, 2H), 3.03 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.18(quin, J=7.5 Hz, 2H), 1.39 (s, 9H), 1.26 (t, J=7.5 Hz, 3H); ESI MS m/z462 [M+H]⁺, and ethyl2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate.MW=361.44. ¹H NMR (CDCl₃, 500 MHz) δ 9.60 (br s, 1H), 7.30-7.27 (m, 2H),7.18-7.14 (m, 2H), 7.10 (s, 1H), 6.84-6.81 (m, 1H), 6.51-6.48 (m, 1H),6.23-6.20 (m, 1H), 5.67 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.61 (s, 2H),2.98 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.17 (quin, J=7.5 Hz,2H), 1.28 (t, J=7.0 Hz, 3H); ESI MS m/z 362 [M+H]⁺.

EXAMPLE 1332-(4-((2-(1H-Pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

A 20-mL vial was charged with tert-butyl2-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-1H-pyrrole-1-carboxylate(0.110 g, 0.24 mmol, 1.0) and methanol (3 mL). To this solution wasadded NH₃ (6.8 mL, 7N in methanol, 476 mmol). The vial was sealed andthe resulting mixture was stirred at 100° C. for 65 h. After this time,the crude reaction solution was concentrated under reduced pressure. Theresidue was adsorbed onto silica then purified by chromatography onsilica using dichloromethane/(90:10:0.25 dichloromethane/methanol/aq.NH₄OH) (10:0 to 0:10) as eluent followed by preparative HPLC(water/acetonitrile with 0.05% TFA) to afford2-(4-((2-(1H-pyrrol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(0.030 g, 38%) as a brown solid. MW=332.40. ¹H NMR (DMSO-d₆, 500 MHz) δ11.16 (br s, 1H), 7.93 (br s, 1H), 7.42 (br s, 1H), 7.26-7.22 (m, 2H),7.17-7.13 (m, 2H), 7.03 (s, 1H), 6.85 (s, 1H), 6.74-6.71 (m, 1H), 6.39(s, 1H), 6.05-6.20 (m, 1H), 3.34 (s, 2H), 2.86 (t, J=7.5 Hz, 2H), 2.78(t, J=7.5 Hz, 2H), 2.05 (quin, J=7.5 Hz, 2H). MS: ESI, m/z 333 [M+H]⁺.Treatment with 1.25M HCl in methanol afforded the title compound (0.035g, 100%) as an off-white solid. MW=368.86. M.p. 163-165° C. ¹H NMR(DMSO-d₆, 500 MHz) δ 13.43 (br s, 1H), 12.06 (br s, 1H), 9.46 (br s,1H), 7.52 (br s, 1H), 7.40-7.36 (m, 2H), 7.32-7.28 (m, 2H), 7.12-7.09(m, 1H), 7.08 (s, 1H), 7.06-7.03 (m, 1H), 6.92 (br s, 1H), 6.29-6.25 (m,1H), 3.43 (s, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.20(quin, J=7.5 Hz, 2H); APCI MS m/z 333 [M+H]⁺.

EXAMPLE 1342-(4-((2-(5-Chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1: Preparation of4-chloro-2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

A 25-mL round bottom flask was charged with2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.59 mmol),5-chloro-3-pyridinyl boronic acid (0.301 g, 1.91 mmol),tetrakis(triphenylphosphine)palladium(0) (0.092 g, 0.08 mmol), andCs₂CO₃ (1.56 g, 4.78 mmol). Toluene (8 ml), EtOH (2 ml) and water (4 ml)were added. The resulting mixture was stirred under Ar at 90° C. for 2.5h. After this time, the mixture was cooled to rt, filtered throughcelite, and the filtrate concentrated under reduced pressure. Theresidue was purified by chromatography on silica using hexane/ethylacetate (10:0 to 0:10) as eluent to afford the title compound (0.127 g,30%) as a white solid. MW=265.14. ¹H NMR (CDCl₃, 500 MHz) δ 8.99 (d,J=2.0 Hz, 1H), 8.59 (d, J=2.5 Hz, 1H), 8.30 (t, J=2.5 Hz, 1H), 7.50 (s,1H), 3.15 (t, J=7.5 Hz, 2H), 3.05 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5Hz, 2H).

Step 2. Preparation of ethyl2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetatehydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.127 g, 0.48 mmol), 4-aminophenyl acetic acid ethyl ester (0.128 g,0.72 mmol), palladium acetate (0.005 g, 0.024 mmol), rac-BINAP (0.022 g,0.036 mmol) and cesium carbonate (0.390 g, 1.20 mmol.) in dioxane (5 mL)under argon. The reaction mixture was absorbed onto silica (4 g) andpurified by chromatography on silica using dichloromethane/methanol(10:0 to 9:1) as eluent to afford the free base of title compound (0.081g). MW=407.89. ¹H NMR (CDCl₃, 500 MHz) δ 8.86 (d, J=1.5 Hz, 1H), 8.52(d, J=2.0 Hz, 1H), 8.22 (t, J=2.0 Hz, 1H), 7.34-7.30 (m, 2H), 7.20-7.16(m, 3H), 4.18 (t, J=7.0 Hz, 2H), 3.62 (s, 2H), 3.09 (t, J=7.5 Hz, 2H),2.85 (t, J=7.5 Hz, 2H), 2.23 (quin, J=7.5 Hz, 2H), 1.28 (t, J=7.5 Hz,3H); ESI MS m/z 408 [M+H]⁺. Further purification by preparative HPLC(water/acetonitrile with 0.05% TFA) and treatment with 2M aqueous HClafforded the title compound (0.074 g, 38%) as a yellow solid. MW=444.35.M.p. 235-237° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.21 (br s, 1H), 9.78 (brs, 1H), 8.90 (d, J=1.5 Hz, 1H), 8.83 (d, J=1.5 Hz, 1H), 8.41 (t, J=2.0Hz, 1H), 7.39 (s, 4H), 7.15 (s, 1H), 4.09 (t, J=7.0 Hz, 2H), 3.72 (s,2H), 3.16 (t, J=7.5 Hz, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.25 (quin, J=7.5Hz, 2H), 1.19 (t, J=7.0 Hz, 3H); APCI MS m/z 408 [M+H]⁺.

EXAMPLE 1342-(4-((2-(5-Chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

A 10-mL vial was charged with ethyl2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.060 g, 0.13 mmol) and ammonium chloride (0.022 g, 0.40 mmol) inmethanol (3 mL). To this mixture was added NH₃ (3.9 mL, 7N in methanol,27.0 mmol). The vial was sealed and the resulting mixture was stirred at100° C. for 72 h. After this time, the mixture was concentrated underreduced pressure and the residue purified by preparative HPLC(water/acetonitrile with 0.05% TFA) followed by chromatography on silicausing dichloromethane/(90:10:0.25 dichloromethane/methanol/aqueousNH₄OH) (10:0 to 0:10) as eluent to afford2-(4-((2-(5-chloropyridin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(0.024 g, 48%) as a white solid. MW=378.85. ¹H NMR (CD₃OD, 300 MHz) δ8.77 (d, J=1.8 Hz, 1H), 8.52 (d, J=2.1 Hz, 1H), 8.20 (t, J=2.1 Hz, 1H),7.36-7.30 (m, 2H), 7.27-7.21 (m, 2H), 7.15 (s, 1H), 3.52 (s, 2H), 3.00(t, J=7.5 Hz, 2H), 2.88 (t, J=7.5 Hz, 2H), 2.19 (quin, J=7.5 Hz, 2H).MS: ESI, m/z 379 [M+H]⁺. Treatment with 1.25 M HCl in methanol (0.25 mL,0.31 mmol) afforded the title compound (0.026 g, 99%) as a yellow solid.MW=415.32. M.p. 193-195° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.32 (br s,1H), 9.85 (br s, 1H), 8.91 (d, J=2.0 Hz, 1H), 8.83 (d, J=2.5 Hz, 1H),8.43 (t, J=2.0 Hz, 1H), 7.51 (s, 1H), 7.40-7.32 (m, 4H), 7.14 (s, 1H),6.91 (s, 1H), 3.42 (s, 2H), 3.17 (t, J=7.0 Hz, 2H), 2.95 (t, J=7.0 Hz,2H), 2.25 (quin, J=7.5 Hz, 2H); ESI MS m/z 379 [M+H]⁺.

EXAMPLE 1352-(4-((2-(3-Hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide:Diastereomer A

Step 1. Preparation of3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone

A 100-mL sealed tube was charged with 3-bromocyclopent-2-enone (2.00 g,12.4 mmol), pinacol diborane (3.47 g, 13.7 mmol), Pd(dppf)Cl₂ (0.72 g,0.88 mmol) and potassium acetate (2.43 g, 24.8 mmol) in dioxane (30 mL).The resulting mixture was heated at 100° C. under argon for 23 h. Afterthis time, the reaction mixture was cooled, filtered through celitewashing solids with ethyl acetate, then concentrated under reducedpressure. The residue was purified by chromatography on silica usinghexanes/ethyl acetate (10:0 to 1:2) as eluent to afford the titlecompound (1.59 g, 61%) as a light yellow solid. MW=208.06. ¹H NMR(CDCl₃, 500 MHz) δ 6.62 (t, J=2.0 Hz, 1H), 2.78-2.74 (m, 2H), 2.37-2.34(m, 2H), 1.32 (s, 12H).

Step 2. Preparation of3-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopent-2-enone

A 250-mL round bottomed flask was charged with2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (1.05 g, 5.58 mmol),3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopent-2-enone (1.27g, 6.14 mmol), tetrakis(triphenylphosphine)palladium(0) (0.322 g, 0.28mmol), and Cs₂CO₃ (5.45 g, 16.7 mmol). Toluene (30 ml), EtOH (7.5 ml)and water (15 ml) were added. The resulting mixture was stirred underargon at 90° C. for 18 h. After cooling to room temperature, thereaction mixture was diluted with ethyl acetate (150 mL), hexanes (50mL) and water (25 mL). The aqueous layer was separated and extractedwith ethyl acetate (2×100 mL). The combined organic extract was washedwith saturated sodium chloride (2×20 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography on silica using hexane/ethyl acetate (10:0 to0:10) as eluent to afford the title compound (0.305 g, 23%) as a yellowsolid. MW=233.69. ¹H NMR (CDCl₃, 500 MHz) δ 7.41 (s, 1H), 6.79 (t, J=2.0Hz, 1H), 3.13 (t, J=7.5 Hz, 2H), 3.10-3.06 (m, 2H), 3.04 (t, J=7.5 Hz,2H), 2.62-2.58 (m, 2H), 2.20 (quin, J=7.5 Hz, 2H).

Step 3. Preparation of3-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopent-2-enol

A 25-mL round bottom flask was charged with3-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopent-2-enone(0.434 g, 1.85 mmol) and THF (8 mL) at rt. Borane-dimethylsulfidecomplex (0.22 mL, 2.32 mmol) was added and the resulting solution wasstirred at 55° C. for 4 h. After this time, the reaction was quenchedwith methanol, treated with 2N aqueous HCl (5 drops), and concentratedunder reduced pressure. The residue was diluted with methanol and thenconcentrated under reduced pressure. The residue was then purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) asthe eluent to afford the title compound (0.123 g, 28%) as an off-whitesolid. MW=235.71. ¹H NMR (CDCl₃, 500 MHz) δ 7.15 (s, 1H), 6.58 (q, J=2.0Hz, 1H), 5.06-4.99 (m, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.99 (t, J=7.5 Hz,2H), 2.97-2.90 (m, 1H), 2.72-2.64 (m, 1H), 2.52-2.44 (m, 1H), 2.15(quin, J=7.5 Hz, 2H), 1.93-1.85 (m, 1H).

Step 4. Ethyl2-(4-((2-(3-hydroxycyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

A 10-mL vial was charged with3-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)cyclopent-2-enol(0.120 g, 0.51 mmol), 4-aminophenylacetic acid ethyl ester (0.096 g,0.53 mmol), palladium acetate (0.006 g, 0.025 mmol), rac-BINAP (0.024 g,0.038 mmol) and cesium carbonate (0.414 g, 1.27 mmol) in dioxane (6 mL)under argon. The reaction mixture was heated to 120° C. under microwaveirradiation for 2 h. The reaction mixture was cooled, and diluted withethyl acetate (75 mL) and water (5 mL). The organic layer was washedwith saturated sodium chloride (2×5 mL), dried over sodium sulfate,filtered, and the filtrate concentrated under reduced pressure. Theresidue was purified by chromatography on silica using 80:20:1dichloromethane/methanol/conc. NH₄OH as the eluent to afford the titlecompound (0.109 g, 56%) as an oil. MW=378.46. ¹H NMR (CDCl₃, 500 MHz) δ7.28 (d, J=8.0 Hz, 2H), 7.14 (d, J=8.0 Hz, 2H), 6.93 (s, 1H), 6.50 (d,J=1.5 Hz, 1H), 5.83 (s, 1H), 5.00-4.94 (m, 1H), 4.18 (q, J=7.0 Hz, 2H),3.61 (s, 2H), 3.03 (t, J=7.5 Hz, 2H), 2.90-2.82 (m, 1H), 2.79 (t, J=7.5Hz, 2H), 2.66-2.58 (m, 1H), 2.46-2.37 (m, 1H), 2.20-2.11 (m, 3H),1.87-1.80 (m, 1H), 1.28 (t, J=7.0 Hz, 3H). ESI m/z 379 [M+H]⁺.

Step 5. Preparation of ethyl2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

A 250-mL round bottom flask was charged with ethyl2-(4-((2-(3-hydroxycyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.109 g, 0.29 mmol) and 10% palladium on carbon (0.028 g) in 1:1 ethylacetate/ethanol (12 mL). This mixture was vigorously stirred under H₂ (1atm) for 4 h. After this time, the mixture was filtered through celiteand the filtrate concentrated under reduced pressure. The residue waspurified by preparative HPLC (water/acetonitrile with 0.05% TFA) toafford two diastereomers of the title compound:

Diastereomer A: (0.022 g, 20%). MW=380.48. ¹H NMR (CDCl₃, 500 MHz) δ7.31-7.27 (m, 2H), 7.17-7.13 (m, 2H), 6.66 (s, 1H), 5.88 (s, 1H), 4.31(t, J=4.0 Hz, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.61 (s, 2H), 3.25-3.18 (m,1H), 2.96 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.5 Hz, 2H), 2.19-2.10 (m, 3H),2.09-2.01 (m, 1H), 1.95-1.78 (m, 3H), 1.73-1.64 (m, 1H), 1.28 (t, J=7.5Hz, 3H). MS: ESI⁺, m/z 381 [M+H]⁺.

Diastereomer B: (0.056 g, 40%). MW=380.48. ¹H NMR (CDCl₃, 500 MHz) δ7.29-7.26 (m, 2H), 7.15-7.11 (m, 2H), 6.71 (s, 1H), 5.79 (s, 1H),4.52-4.47 (m, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.61 (s, 2H), 3.44-3.35 (m,1H), 3.01 (t, J=7.5 Hz, 2H), 2.75 (t, J=7.5 Hz, 2H), 2.22-2.10 (m, 4H),2.05-1.98 (m, 2H), 1.94-1.74 (m, 2H), 1.73-1.61 (m, 1H), 1.28 (t, J=7.5Hz, 3H); ESI MS m/z 381 [M+H]⁺.

EXAMPLE 1362-(4-((2-(3-Hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(Diastereomer A)

A 10-mL vial was charged with ethyl2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(diastereomer A, 0.022 g, 0.058 mmol), methanol (2 mL) and ammonia (1.7mL, 7N in methanol, 11.5 mmol). The vial was sealed and the resultingmixture was stirred at 100° C. for 23 h. After this time, LCMS analysisof the cooled reaction showed ˜88% conversion. Additional ammonia (1.0mL, 7N in methanol, 7.0 mmol) was added and the mixture was heated at100° C. for 2 h. Then, the cooled reaction mixture was concentratedunder reduced pressure. The residue was absorbed on silica (2 g) andpurified by chromatography on silica using dichloromethane/(80:20:1dichloromethane/methanol/conc. NH₄OH) (10:0 to 0:10) as eluent to affordthe title compound (0.005 g, 25%) as a light brown solid. MW=351.44 ¹HNMR (DMSO-d₆, 500 MHz) δ 7.86 (s, 1H), 7.41 (s, 1H), 7.23-7.19 (m, 2H),7.12-7.08 (m, 2H), 6.84 (br s, 1H), 6.60 (s, 1H), 4.39 (d, J=4.0 Hz,1H), 4.25-4.20 (m, 1H), 3.33 (s, 2H), 3.18 (quin, J=6.5 Hz, 1H), 2.78(t, J=7.5 Hz, 2H), 2.73 (t, J=7.5 Hz, 2H), 2.05-1.88 (m, 4H), 1.83-1.72(m, 2H), 1.67-1.56 (m, 1H), 1.53-1.45 (m, 1H); APCI m/z 352 [M+H]⁺.

EXAMPLE 1372-(4-((2-(3-Hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(Diastereomer B)

A 10-mL vial was charged with ethyl2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(Diastereomer B, 0.056 g, 0.147 mmol), methanol (3 mL) and ammonia (4.2mL, 7N in methanol, 29.4 mmol). The vial was sealed and the resultingmixture was stirred at 100° C. for 23 h. LCMS analysis of the cooledreaction showed ˜66% conversion. Additional ammonia (1.0 mL, 7N inmethanol, 7.0 mmol) was added and the mixture was heated at 100° C. for2 h. The cooled reaction mixture solution was concentrated under reducedpressure. The residue was absorbed on silica (4 g) then purified bychromatography on silica using dichloromethane/(80:20:1dichloromethane/methanol/conc. NH₄OH) (10:0 to 0:10) as the eluent toafford the title compound (0.034 g, 67%) as an off-white solid.MW=351.44. M.p. 93-95° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.95 (s, 1H), 7.42(s, 1H), 7.24-7.20 (m, 2H), 7.13-7.09 (m, 2H), 6.85 (br s, 1H), 6.64 (s,1H), 5.60 (br s, 1H), 4.13-4.07 (m, 1H), 3.33 (s, 2H), 3.03 (quin, J=7.7Hz, 1H), 2.78 (t, J=7.5 Hz, 2H), 2.74 (t, J=7.0 Hz, 2H), 2.09-1.98 (m,3H), 1.95-1.86 (m, 1H), 1.77-1.56 (m, 4H). MS: APCI, m/z 352 [M+H]⁺.

EXAMPLE 1382-(4-((2-(3-Cyanocyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

A 25-mL round bottom flask was charged with2-(4-((2-(3-hydroxycyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(Diastereomer B, 0.030 g, 0.085 mmol) and triphenylphosphine (0.112 g,0.43 mmol) and acetone cyanohydrin (0.039 mL, 0.43 mmol) in THF. To thisstirred solution at 0° C. was added di-tert-butyl azodicarboxylate(0.098 g, 0.43 mmol). After stirring for 24 h, the reaction mixture wasabsorbed onto silica (2 g) and was purified by chromatography on silicausing dichloromethane/methanol (10:0 to 9:1) as the eluent to afford2-(4-((2-(3-cyanocyclopentyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(Diastereomer A: 0.021 g, 68%) as a colorless oil. MW=360.45. ¹H NMR(CD₃OD, 300 MHz) δ 7.34-7.28 (m, 2H), 7.20-7.14 (m, 2H), 6.69 (s, 1H),3.50 (s, 2H), 3.28-3.10 (m, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5Hz, 2H), 2.23-2.08 (m, 6H), 2.00-1.86 (m, 1H), 1.83-1.67 (m, 1H); ESI MSm/z 361 [M+H]⁺. Treatment with 1.25M HCl in methanol (0.093 mL, 0.115mmol) afforded the title compound (Diastereomer A: 0.020 g, 89%) as awhite solid. MW=396.91. M.p. 215-217° C. decomp. ¹H NMR (DMSO-d₆, 500MHz) δ 13.74 (br s, 1H), 9.47 (br s, 1H), 7.50 (s, 1H), 7.37-7.31 (m,2H), 7.27-7.20 (m, 2H), 6.90 (s, 1H), 6.72 (s, 1H), 3.40 (s, 2H), 3.03(br s, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.32-2.05 (m, 7H), 1.89-1.80 (m,1H), 1.77-1.65 (m, 1H); APCI MS m/z 361 [M+H]⁺.

EXAMPLE 1392-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of 2,4-dichloro-6-cyclopropylpyridine

A 250-mL round bottomed flask was charged with 2,4,6-trichloropyridine(2.50 g, 13.7 mmol), cyclopropylboronic acid (1.29 g, 15.1 mmol),palladium acetate (0.307 g, 1.37 mmol), tricyclhexylphosphine (0.768 g,2.74 mmol) and K₃PO₄ (10.2 g, 47.9 mmol). Toluene (75 ml) and water (4ml) were added. The resulting mixture was stirred under Ar at 90° C. for24 h. After cooling to room temperature, the reaction mixture wasdiluted with water (50 mL) and dichloromethane (50 mL). The mixture wasfiltered through celite washing solids with dichloromethane. The aqueouslayer was separated and extracted with dichloromethane (3×50 mL). Thecombined organic extract was washed with saturated sodium chloride (25mL) then dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by chromatography on silicausing hexane/dichloromethane (100:0 to 0:100) as eluent to afford anapproximate 1:2 mixture of trichloropyridine and2,4-dichloro-6-cyclopropylpyridine (1.09 g, 42%) as a colorless oil.MW=188.05. ¹H NMR (CDCl₃, 500 MHz) δ 7.08 (d, J=2.0 Hz, 1H), 7.05 (d,J=2.0 Hz, 1H), 2.00-1.93 (m, 1H), 1.09-1.00 (m, 4H). This was usedwithout further manipulation.

Step 2. Preparation of 4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyridine

A 250-mL round bottomed flask was charged with2,4-dichloro-6-cyclopropylpyridine (1.08 g, 5.74 mmol),(3-chlorophenyl)boronic acid (0.99 g, 6.32 mmol),tetrakis(triphenylphosphine)palladium(0) (0.332 g, 0.28 mmol), andCs₂CO₃ (5.61 g, 17.2 mmol). Toluene (40 ml), EtOH (10 ml) and water (20ml) were added. The resulting mixture was stirred under Ar at 90° C. for23 h. After cooling to room temperature, the reaction mixture wasdiluted with water (50 mL) and dichloromethane (50 mL). The mixture wasfiltered through celite washing solids with dichloromethane. The aqueouslayer was separated and extracted with dichloromethane (2×50 mL). Thecombined organic extract was washed with saturated sodium chloride (25mL) then dried over sodium sulfate, filtered, and concentrated underreduced pressure. The residue was purified by chromatography on silicausing hexane/dichloromethane (100:0 to 0:100) as eluent to afford thetitle compound (0.30 g, 20%) as a colorless oil. MW=264.15. ¹H NMR(CDCl₃, 500 MHz) δ 7.98-7.96 (m, 1H), 7.85-7.80 (m, 1H), 7.45 (d, J=1.5Hz, 1H), 7.39-7.35 (m, 2H), 7.12 (d, J=1.5 Hz, 1H), 2.18-2.01 (m, 1H),1.18-1.12 (m, 2H), 1.06-1.00 (m, 2H).

Step 3. Preparation of ethyl2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetate

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyridine (0.300 g, 1.14 mmol),4-aminophenyl acetic acid ethyl ester (0.203 g, 1.14 mmol), palladiumacetate (0.013 g, 0.057 mmol), rac-BINAP (0.053 g, 0.085 mmol) andcesium carbonate (0.925 g, 2.84 mmol) in dioxane (6 mL) under argon. Thereaction mixture was heated to 120° C. under microwave irradiation for 2h. After this time, the reaction mixture was cooled, diluted with ethylacetate (25 mL) and water (25 mL). The aqueous layer was extracted withethyl acetate (25 mL). The combined extract was washed with saturatedsodium chloride (2×5 mL), dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated under reduced pressure. The residuewas purified by chromatography on silica using hexanes/ethyl acetate(10:0 to 0:10) to afford the title compound (0.152 g, 33%) as acolorless oil. MW=406.90. ¹H NMR (CDCl₃, 500 MHz) δ 7.94-7.92 (m, 1H),7.80-7.76 (m, 1H), 7.34-7.31 (m, 2H), 7.31-7.27 (m, 2H), 7.18-7.15 (m,2H), 6.66 (d, J=2.5 Hz, 1H), 5.96 (s, 1H), 4.18 (q, J=7.5 Hz, 2H), 3.61(s, 2H), 1.99-1.92 (m, 1H), 1.28 (t, J=7.0 Hz, 3H), 1.13-1.08 (m, 2H),0.96-0.91 (m, 2H); ESI MS m/z 407 [M+H]⁺.

EXAMPLE 1392-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetamidehydrochloride

A 20-mL vial was charged with ethyl2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetate(0.090 g, 0.23 mmol), dioxane (1 mL) and methanol (3 m). To thissolution was added NH₃ (6.0 mL, 7N in methanol, 42.0 mmol). The vial wassealed and the resulting mixture was stirred at 100° C. for 47 h. Thecrude reaction mixture was concentrated under reduced pressure. Theresidue was adsorbed onto silica then purified by chromatography onsilica using hexanes/ethyl acetate (10:0 to 0:10) as eluent followed bychromatography on silica using dichloromethane/methanol (10:0 to 9:1) aseluent to afford2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetamide(0.024 g, 27%) as a colorless oil. MW=377.87. ¹H NMR (CDCl₃, 500 MHz) δ7.94-7.91 (m, 1H), 7.81-7.76 (m, 1H), 7.36-7.31 (m, 2H), 7.30-7.26 (m,2H), 7.21-7.17 (m, 2H), 7.01 (d, J=2.0 Hz, 1H), 6.68 (d, J=2.5 Hz, 1H),6.02 (s, 1H), 5.45 (br s, 2H), 3.58 (s, 2H), 1.99-1.93 (m, 1H),1.13-1.08 (m, 2H), 0.97-0.92 (m, 2H); ESI MS m/z 378 [M+H]⁺. Treatmentwith 1.25M HCl (0.103 mL, 0.130 mol) in methanol afforded the titlecompound (0.022 g, 84%) as an off-white solid. MW=414.33. M.p. 104-106°C. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.48 (br s, 1H), 8.78 (br s, 1H), 7.92(d, J=1.0 Hz, 1H), 7.84-7.76 (m, 1H), 7.52 (br s, 2H), 7.45 (s, 1H),7.30-7.25 (m, 2H), 7.25-7.16 (m, 2H), 7.11 (s, 1H), 6.87 (s, 1H), 6.74(s, 1H), 3.36 (s, 2H), 2.15-2.02 (m, 1H), 1.10-0.90 (m, 4H); ESI MS m/z378 [M+H]⁺.

EXAMPLE 1402-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)ethanolhydrochloride

A 25-mL round bottom flask was charged with ethyl2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)acetate(0.152 g, 0.37 mmol) and THF (6 mL) at rt. Borane-dimethylsulfidecomplex (0.106 mL, 1.12 mmol) was added and the resulting solution wasstirred at 50° C. for 2.5 h until the starting material was consumed(monitored by LCMS analysis). The reaction was quenched with methanolthen treated with 2N aqueous HCl (5 drops) and concentrated underreduced pressure. The residue was diluted with methanol and thenconcentrated under reduced pressure. The residue was treated withsaturated sodium bicarbonate (0.1 mL) and then purified by columnchromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) asthe eluent to afford2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyridin-4-yl)amino)phenyl)ethanol(0.107 g, 78%) as a colorless oil. MW=364.87. ¹H NMR (CDCl₃, 500 MHz) δ7.94-7.92 (m, 1H), 7.81-7.76 (m, 1H), 7.35-7.30 (m, 2H), 7.27-7.23 (m,2H), 7.18-7.14 (m, 2H), 6.99 (d, J=2.0 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H),5.94 (s, 1H), 3.90 (q, J=6.0 Hz, 2H), 2.88 (t, J=1.5 Hz, 2H), 1.99-1.92(m, 1H), 1.40 (t, J=2.0 Hz, 1H), 1.12-1.07 (m, 2H), 0.96-0.90 (m, 2H);ESI MS m/z 365 [M+H]⁺. Treatment with 1.25M HCl in methanol (0.70 mL,0.88 mmol) afforded the title compound (0.105 g, 90%) as a light yellowsolid. MW=401.33. M.p. 125-128° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.57 (brs, 1H), 10.50 (br s, 1H), 7.95-7.93 (m, 1H), 7.77-7.73 (m, 1H),7.72-7.66 (m, 1H), 7.65-7.59 (m, 1H), 7.34-7.29 (m, 2H), 7.28-7.24 (m,2H), 7.07 (s, 1H), 6.58 (br s, 1H), 3.63 (t, J=7.0 Hz, 2H), 2.74 (t,J=7.0 Hz, 2H), 2.40-2.29 (m, 1H), 1.22 (s, 2H), 1.05-0.96 (m, 2H); APCIMS m/z 365 [M+H]⁺.

EXAMPLE 141 AND EXAMPLE 142 Methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetateand2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)aceticacid

Step 1. Preparation of4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine

A 500-mL round bottomed flask was charged with2,4-dichloro-6-trifluoromethylpyridine (2.00 g, 9.26 mmol),(3-chlorophenyl)boronic acid (1.59 g, 10.2 mmol),tetrakis(triphenylphosphine)palladium(0) (0.535 g, 0.46 mmol), andCs₂CO₃ (9.05 g, 27.8 mmol). Toluene (40 ml), EtOH (10 ml) and water (20ml) were added. The resulting mixture was stirred under Ar at 90° C. for4 h. After cooling to room temperature, the reaction mixture was dilutedwith ethyl acetate (100 mL) and hexanes (100 mL). The aqueous layer wasseparated and the organic layer was washed with saturated sodiumchloride (2×25 mL), dried over sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified bychromatography on silica using hexane/ethyl acetate (100:1 to 95:5) aseluent followed by chromatography on silica using hexane/dichloromethane(100:0 to 80:20) as eluent to afford the title compound (1.48 g, 55%) asa white solid. MW=292.08. ¹H NMR (CDCl₃, 500 MHz) δ 8.06-8.04 (m, 1H),7.92 (dt, J=7.0, 2.0 Hz, 1H), 7.89 (d, J=1.5 Hz, 1H), 7.64 (d, J=1.5 Hz,1H), 7.48-7.42 (m, 2H).

EXAMPLE 141 AND EXAMPLE 142 Methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetateand2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)aceticacid

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.263 g, 0.90mol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.261 g, 0.90 mmol), Pd(dppf)Cl₂ (0.073 g, 0.09 mmol), and powderedNa₂CO₃ (0.286 g, 2.70 mmol). Dioxane (8 mL) and water (4 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 27 h. until thestarting chloride was consumed. After cooling to room temperature, thereaction mixture was absorbed onto silica and purified by chromatographyon silica using dichloromethane/methanol (10:0 to 9:1) as eluent toafford methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetate

EXAMPLE 141

(0.018 g, 4%) as a light brown solid. MW=419.82. M.p. 72-74° C. ¹H NMR(CDCl₃, 500 MHz) δ 8.03-8.00 (m, 1H), 7.91-7.86 (m, 1H), 7.68 (s, 1H),7.46-7.44 (m, 1H), 7.42-7.37 (m, 2H), 7.29-7.26 (m, 2H), 7.18-7.15 (m,2H), 4.09 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H); APCI MS m/z 420 [M+H]⁺.

EXAMPLE 142

(0.396 g). Prep HPLC of sample (0.055 g) afforded2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)aceticacid (0.027 g, 7%) as a white solid. MW=405.80. M.p. 124-126° C. ¹H NMR(CDCl₃, 500 MHz) δ 8.03-8.00 (m, 1H), 7.91-7.85 (m, 1H), 7.68 (s, 1H),7.46-7.44 (m, 1H), 7.42-7.37 (m, 2H), 7.30-7.26 (m, 2H), 7.19-7.15 (m,2H), 4.09 (s, 2H), 3.65 (s, 2H); APCI MS m/z 406 [M+H]⁺.

EXAMPLE 1432-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)ethanol

A 50-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetate(0.165 g, 0.40 mmol) and THF (10 mL) at rt. Borane-dimethylsulfidecomplex (0.154 mL, 1.62 mmol) was added and the resulting solution wasstirred at 55° C. for 3 h. After this time, the reaction was quenchedwith methanol then treated with 2N aqueous HCl (5 drops), andconcentrated under reduced pressure. The residue was diluted withmethanol and then concentrated under reduced pressure. The residue waspurified by column chromatography on silica using hexanes/ethyl acetate(10:0 to 1:1) as the eluent followed by column chromatography on silicausing hexanes/dichloromethane (10:0 to 0:10) as the eluent to afford thetitle compound (0.064 g, 18%) as a colorless gum. MW=391.81. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.33 (s, 1H), 8.17-8.15 (m, 1H), 8.11-8.06 (m, 1H),7.77 (d, J=0.5 Hz, 1H), 7.60-7.54 (m, 2H), 7.28 (d, J=8.0 Hz, 2H), 7.16(d, J=8.0 Hz, 2H), 4.58 (t, J=5.0 Hz, 1H), 4.12 (s, 2H), 3.59-3.54 (m,2H), 2.67 (t, J=5.0 Hz, 2H); APCI MS m/z 392 [M+H]⁺.

EXAMPLE 1442-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)acetamide

An 100-mL round bottom flask was charged with2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)methyl)phenyl)aceticacid (0.17 g, 0.42 mmol) in dichloromethane (10 ml). To this solution at0° C. was added oxalyl chloride (0.18 mL, 2.10 mmol) followed by DMF (1drop). After stirring for 5 h the volatile material was removed underreduced pressure to afford crude acid chloride. The residue wasdissolved in dichloromethane (10 mL), cooled to 0° C., and 7N ammonia inmethanol (10.0 mL, 70 mmol) was added. After stirring for 0.5 h, thevolatile material was removed under reduced pressure. The residue waspurified by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as eluent followed by chromatography on silica usingdichloromethane/methanol (10:0 to 9:1) as eluent to afford the titlecompound (0.079 g, 21%) as an off-white solid. MW=404.81. M.p. 148-160°C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.33 (s, 1H), 8.17-8.15 (m, 1H),8.11-8.05 (m, 1H), 7.76 (d, J=0.5 Hz, 1H), 7.60-7.55 (m, 2H), 7.41 (brs, 1H), 7.31 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H),4.11 (s, 2H), 3.32 (s, 2H); APCI MS m/z 405 [M+H]⁺.

EXAMPLE 1452-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of ethyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.150 g, 0.51mmol), 4-aminophenyl acetic acid ethyl ester (0.138 g, 0.77 mmol),palladium acetate (0.006 g, 0.026 mmol), rac-BINAP (0.024 g, 0.038 mmol)and cesium carbonate (0.418 g, 1.28 mmol) in dioxane (5 mL) under argon.The reaction mixture was heated to 120° C. under microwave irradiationfor 2 h. After this time, the reaction mixture was cooled and absorbedonto silica (4 g). Purification by chromatography on silica usinghexanes/ethyl acetate (10:0 to 0:10) as eluent followed by preparativeHPLC (water/acetonitrile with 0.05% TFA) afforded the title compound(0.064 g, 28%) as a tacky solid. MW=434.84. ¹H NMR (CDCl₃, 300 MHz) δ9.39 (s, 1H), 8.00-7.97 (m, 1H), 7.93-7.86 (m, 1H), 7.57-7.52 (m, 3H),7.35-7.25 (m, 4H), 7.21 (d, J=3.0 Hz, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.67(s, 3H), 1.20 (t, J=7.2 Hz, 3H); ESI MS m/z 435 [M+H]⁺.

EXAMPLE 1452-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetamide

A 10-mL vial was charged with ethyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate(0.064 g, 0.15 mmol) and ammonium chloride (0.024 g, 0.44 mmol) inmethanol (2 mL). To this mixture was added NH₃ (4.2 mL, 7N in methanol,29.4 mmol). The vial was sealed and the resulting mixture was stirred at100° C. for 42 h. After this time, the crude reaction solutionconcentrated under reduced pressure. The residue absorbed on silica (2g) then purified by chromatography on silica usingdichloromethane/methanol (10:0 to 9:1) as eluent to afford the titlecompound (0.027 g, 46%) as a light brown solid. MW=405.80. M.p. 97-99°C. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.39 (s, 1H), 7.99-7.97 (m, 1H),7.91-7.86 (m, 1H), 7.57-7.51 (m, 3H), 7.46 (br s, 1H), 7.33-7.29 (m,2H), 7.27-7.23 (m, 2H), 7.19 (d, J=2.0 Hz, 1H), 6.88 (br s, 1H), 3.37(s, 2H); APCI MS m/z 406 [M+H]⁺.

EXAMPLE 1462-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)ethanol

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.140 g, 0.48mmol), 4-aminophenethyl alcohol (0.099 g, 0.72 mmol), palladium acetate(0.005 g, 0.024 mmol), rac-BINAP (0.022 g, 0.036 mmol) and cesiumcarbonate (0.390 g, 1.20 mmol) in dioxane (5 mL) under argon. Thereaction mixture was heated to 120° C. under microwave irradiation for 2h. The reaction mixture was cooled, and absorbed onto silica (5 g).Purification by chromatography on silica using hexanes/ethyl acetate(10:0 to 0:10) as eluent followed by preparative HPLC(water/acetonitrile with 0.05% TFA) afforded the title compound (0.093g, 50%) as a pale yellow solid. MW=392.80. M.p. 60-62° C. ¹H NMR(DMSO-d₆, 500 MHz) δ 9.30 (s, 1H), 7.99-7.96 (m, 1H), 7.91-7.86 (m, 1H),7.57-7.51 (m, 2H), 7.50 (d, J=2.0 Hz, 1H), 7.30-7.26 (m, 2H), 7.24-7.20(m, 2H), 7.18 (d, J=2.0 Hz, 1H), 4.64 (t, J=5.0 Hz, 1H), 3.67-3.58 (m,2H), 2.73 (t, J=7.0 Hz, 2H); ESI MS m/z 393 [M+H]⁺.

EXAMPLE 1473-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)propan-1-ol

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyridine (0.120 g, 0.41mmol), 4-aminophenpropyl alcohol (0.093 g, 0.61 mmol), palladium acetate(0.005 g, 0.021 mmol), rac-BINAP (0.019 g, 0.031 mmol) and cesiumcarbonate (0.335 g, 1.02 mmol) in dioxane (5 mL) under argon. Thereaction mixture was heated to 120° C. under microwave irradiation for 4h. After this time, the reaction mixture was cooled and diluted withwater (5 mL) and ethyl acetate (100 mL). The organic layer was washedwith saturated sodium chloride (2×5 mL), dried over sodium sulfate,filtered, and the filtrate concentrated under reduced pressure. Theresidue was purified by chromatography on silica using hexanes/ethylacetate (10:0 to 0:10) as eluent to afford the title compound (0.024 g,15%) as an off-white solid. MW=406.83. M.p. 46-48° C. ¹H NMR (DMSO-d₆,500 MHz) δ 9.28 (s, 1H), 7.98-7.96 (m, 1H), 7.91-7.86 (m, 1H), 7.56-7.51(m, 2H), 7.49 (d, J=2.0 Hz, 1H), 7.26 (d, J=8.5 Hz, 2H), 7.22 (d, J=8.5Hz, 2H), 7.17 (d, J=2.0 Hz, 1H), 4.46 (t, J=5.0 Hz, 1H), 3.43 (q, J=6.0Hz, 2H), 2.62 (t, J=7.5 Hz, 2H), 1.77-1.59 (m, 2H); APCI MS m/z 407[M+H]⁺.

EXAMPLE 1482-(4-((2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.350 g, 1.86 mmol)was reacted with (4-chlorophenyl)boronic acid (0.378 g, 2.42 mmol) toafford the title compound (0.355 g, 78%). MW=264.15. ¹H NMR (CD₃OD, 300MHz) δ 7.96-7.83 (m, 2H), 7.61 (d, J=4.6 Hz, 1H), 7.51-7.39 (m, 2H),3.13-2.99 (m, 4H), 2.25-2.14 (m, 2H); APCI MS m/z 264 [M+H]⁺.

Step 2. Preparation of ethyl2-(4-((2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following General Procedure B2,4-chloro-2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.100g, 0.38 mmol) was reacted with 4-aminophenylacetic acid ethyl ester(0.102 g, 0.57 mmol) to afford the title compound (0.075 g, 38%) as ayellow oil. MW=406.90. APCI MS m/z 407 [M+H]⁺.

EXAMPLE 1482-(4-((2-(4-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following General Procedure C, ethyl2-(4-((2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.075 g, 0.18 mmol) was reacted with ammonia in methanol (7 M, 4 mL),followed by the formation of the hydrochloride salt to form the titlecompound (0.017 g, 22%) as an off-white solid. MW=414.33. ¹H NMR(DMSO-d₆, 300 MHz) δ 14.03 (s, 1H), 9.80 (s, 1H), 7.83-7.75 (m, 2H),7.70-7.63 (m, 2H), 7.54 (s, 1H), 7.42-7.30 (m, 4H), 6.98 (s, 1H), 6.94(s, 1H), 3.42 (s, 2H), 3.16 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H),2.31-2.18 (m, 2H); APCI MS m/z 378 [M+H]⁺.

EXAMPLE 1492-(4-((2-(4-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure B2, ethyl2-(4-((2-(4-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.100 g, 0.38 mmol) was reacted with 4-aminophenethyl alcohol (0.078 g,0.57 mmol) followed by the formation of the hydrochloride salt to affordthe title compound (0.030 g, 30%) as a yellow solid. MW=401.33. ¹H NMR(DMSO-d₆, 300 MHz) δ 13.99 (s, 1H), 9.77 (s, 1H), 7.82-7.73 (m, 2H),7.70-7.62 (m, 2H), 7.39-7.27 (m, 4H), 6.95 (s, 1H), 3.64 (t, J=6.8 Hz,2H), 3.15 (t, J=7.7 Hz, 2H), 2.91 (t, J=7.6, 2H), 2.76 (t, J=7.6 Hz,2H), 2.30-2.15 (m, 2H); APCI MS m/z 365 [M+H]⁺.

EXAMPLE 1502-(4-((2-(3-Chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol)in toluene/ethanol/water (6 mL:3 mL:1 mL) was reacted with(3-chloro-4-fluorophenyl)boronic acid (0.362 g, 2.07 mmol) to afford thetitle compound (0.289 g, 96%) as a white solid. MW=282.14. ¹H NMR(CD₃OD, 300 MHz) δ 8.15-8.07 (m, 1H), 7.94-7.86 (m, 1H), 7.66 (s, 1H),7.33 (t, J=8.8 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 3.04 (t, J=7.6 Hz, 2H),2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 282 [M+H]⁺.

Step 2. Preparation of ethyl2-(4-((2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following General Procedure B2,4-chloro-2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.100 g, 0.35 mmol) was reacted with 4-aminophenylacetic acid ethylester (0.095 g, 0.53 mmol) to afford the title compound (0.142 g, 71%).MW=424.90. ¹H NMR (CD₃OD, 300 MHz) δ 7.91-7.84 (m, 1H), 7.70-7.60 (m,1H), 7.49-7.39 (m, 3H), 7.39-7.32 (m, 2H), 6.98 (s, 1H), 4.16 (q, J=7.1Hz, 2H), 3.71 (s, 2H), 3.33-3.29 (m, 2H), 3.21 (t, J=7.6 Hz, 2H), 3.00(t, J=7.6 Hz, 2H), 2.37 (quin, J=7.6 Hz, 3H); APCI MS m/z 425 [M+H]⁺.

EXAMPLE 1502-(4-((2-(3-Chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following General Procedure C, ethyl2-(4-((2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.075 g, 0.18 mmol) was reacted with ammonia in methanol (7 M, 4 mL),followed by the formation of the hydrochloride salt to afford the titlecompound (0.028 g, 37%) as a brown solid. MW=432.32. ¹H NMR (DMSO-d₆,300 MHz) δ 14.06 (s, 1H), 9.80 (s, 1H), 8.14-8.07 (m, 1H), 7.82-7.74 (m,1H), 7.65 (t, J=8.9 Hz, 1H), 7.54 (s, 1H), 7.41-7.32 (m, 4H), 7.01 (s,1H), 6.94 (s, 1H), 3.42 (s, 2H), 3.15 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6Hz, 2H), 2.33-2.17 (m, 2H); APCI MS m/z 396 [M+H]⁺.

EXAMPLE 1512-(4-((2-(3-Chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure B2, ethyl2-(4-((2-(3-chloro-4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.110 g, 0.39 mmol) was reacted with 4-aminophenethyl alcohol (0.080 g,0.58 mmol), followed by the formation of the hydrochloride salt toafford the title compound (0.011 g, 15%) as an off-white solid.MW=405.29. ¹H NMR (DMSO-d₆, 300 MHz) δ 14.04 (s, 1H), 9.74 (s, 1H),8.18-8.01 (m, 1H), 7.81-7.72 (m, 1H), 7.64 (t, J=8.9 Hz, 1H), 7.38-7.27(m, 4H), 6.99 (s, 1H), 3.64 (t, J=6.8 Hz, 2H), 3.14 (t, J=7.6 Hz, 2H),2.92 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.8 Hz, 2H) 2.31-2.16 (m, 2H), 1.24(s, 1H); APCI MS m/z 383 [M+H]⁺.

EXAMPLE 1522-(4-((2-(3-Chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.250 g, 1.33 mmol)was reacted with (3-chloro-5-fluorophenyl)boronic acid (0.301 g, 2.07mmol), to afford the title compound (0.224 g, 90%) as a white solid.MW=282.14. ¹H NMR (CD₃OD, 300 MHz) δ 7.87-7.84 (m, 1H), 7.72-7.65 (m,2H), 7.30-7.21 (m, 1H), 3.17-3.00 (m, 4H), 2.21 (quin, J=7.6 Hz, 2H);APCI MS m/z 282 [M+H]⁺.

Step 2. Preparation of ethyl2-(4-((2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following General Procedure B2,4-chloro-2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.100 g, 0.36 mmol) was reacted with 4-aminophenylacetic acid ethylester (0.096 g, 0.53 mmol) to afford the title compound (0.086 g, 87%)as a yellow oil. MW=424.90. ¹H NMR (CD₃OD, 300 MHz) δ 7.54 (s, 1H),7.43-7.34 (m, 1H), 7.31 (s, 1H), 7.28 (s, 1H), 7.25-7.13 (m, 3H),7.10-7.06 (m, 1H), 5.48 (s, 1H), 4.21-4.07 (m, 2H), 3.69 (s, 2H), 2.98(t, J=7.6 Hz, 2H), 2.86 (t, J=7.6 Hz, 2H), 2.17 (quin, J=7.6, 2H),1.37-1.17 (m, 3H); APCI MS m/z 425 [M+H]⁺.

EXAMPLE 1522-(4-((2-(4-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following General Procedure C, ethyl2-(4-((2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.086 g, 0.20 mmol) was reacted with ammonia in methanol (7 M, 4 mL),followed by the formation of the hydrochloride salt to afford the titlecompound (0.024 g, 29%) as a yellow solid. MW=432.32. ¹H NMR (DMSO-d₆,300 MHz) δ 14.19 (s, 1H), 9.79 (s, 1H), 7.82-7.77 (m, 1H), 7.77-7.67 (m,2H), 7.54 (s, 1H), 7.36 (s, 4H), 7.08 (s, 1H), 6.93 (s, 1H), 3.42 (s,2H), 3.15 (t, J=7.6 Hz, 2H), 2.93 (t, J=7.6 Hz, 2H), 2.31-2.16 (m, 2H);APCI MS m/z 396 [M+H]⁺.

EXAMPLE 1532-(4-((2-(3-Chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure B2, ethyl2-(4-((2-(3-chloro-5-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.075 g, 0.27 mmol) was reacted with 4-aminophenethyl alcohol (0.055 g,0.40 mmol), followed by the formation of the hydrochloride salt toafford the title compound (0.017 g, 23%) as a yellow solid. MW=419.32.¹H NMR (DMSO-d₆, 300 MHz) δ 14.06 (s, 1H), 9.77 (s, 1H), 7.79-7.76 (m,1H), 7.75-7.72 (m, 1H), 7.71-7.68 (m, 1H), 7.33 (s, 4H), 7.05 (s, 1H),3.64 (t, J=6.9 Hz, 3H), 3.15 (t, J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H),2.76 (t, J=6.9 Hz, 2H), 2.30-2.17 (m, 2H); APCI MS m/z 383 [M+H]⁺.

EXAMPLE 1542-(4-((2-(3,4-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Step 1. Preparation of4-chloro-2-(3,4-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol)was reacted with (3,4-dichlorophenyl)boronic acid (0.198 g, 1.04 mmol)to afford the title compound (0.141 g, 94%). MW=298.59. ¹H NMR (CD₃OD,300 MHz) δ 8.16 (d, J=2.1 Hz, 1H), 7.90-7.84 (m, 1H), 7.69 (s, 1H), 7.61(d, J=8.5 Hz, 1H), 3.12 (t, J=7.6 Hz, 2H), 3.05 (t, J=7.6 Hz, 2H), 2.21(quin, J=7.6 Hz, 2H); APCI MS m/z 297 [M+H]⁺.

EXAMPLE 1542-(4-((2-(3,4-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure B2, ethyl2-(4-((2-(3,4-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-yl)amino)phenyl)acetate(0.075 g, 0.25 mmol) was reacted with 4-aminophenethyl alcohol (0.052 g,0.38 mmol), followed by the formation of the hydrochloride salt toafford the title compound (0.018 g, 25%) as an off-white solid.MW=435.77. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.40 (s, 1H), 9.77 (s, 1H), 8.15(d, J=2.2 Hz, 1H), 7.82 (d, J=8.5 Hz, 1H), 7.77-7.73 (m, 1H), 7.32 (s,4H), 7.04 (s, 1H), 4.67 (s, 1H), 3.63 (t, J=7.0 Hz, 2H), 3.14 (t, J=7.6Hz, 2H), 2.91 (t, J=7.6 Hz, 2H), 2.76 (t, J=7.6 Hz, 2H), 2.26-2.14 (m,2H); APCI MS m/z 399 [M+H]⁺.

EXAMPLE 1552-(4-((2-(2,5-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol)was reacted with (2,5-dichlorophenyl)boronic acid (0.396 g, 2.07 mmol),followed by the formation of the hydrochloride salt to afford the titlecompound (0.285 g, 95% yield) as a white solid. MW=335.06. ¹H NMR(CDCl₃, 300 MHz) δ 13.09 (s, 1H), 7.56 (d, J=2.4 Hz, 1H), 7.45-7.37 (m,2H), 7.33-7.29 (m, 1H), 3.16 (t, J=7.6 Hz, 2H), 3.06 (t, J=7.6 Hz, 2H),2.21 (quin, J=7.6 Hz, 2H); APCI MS m/z 297 [M+H]⁺.

EXAMPLE 1552-(4-((2-(2,5-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following General Procedure A1,4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with2-(4-aminophenyl)acetamide (0.060 g, 0.40 mmol), followed by theformation of the hydrochloride salt to afford the title compound (0.009g, 10%) as a tan solid. MW=448.77. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.18 (s,1H), 10.16 (s, 1H), 7.79 (s, 1H), 7.71-7.64 (m, 2H), 7.50 (d, J=8.5 Hz,1H), 7.42 (d, J=8.5 Hz, 1H), 7.31 (d, J=8.0 Hz, 1H), 7.16 (d, J=8.5 Hz,1H), 6.91 (s, 1H), 3.66 (s, 2H), 3.30 (s, 2H), 3.15-3.06 (m, 2H),3.0-2.89 (m, 2H), 2.31-2.19 (m, 2H); APCI MS m/z 412 [M+H]⁺.

EXAMPLE 1562-(4-((2-(2,5-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure A1,4-chloro-2-(2,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with 4-aminophenethylalcohol (0.055 g, 0.40 mmol), followed by the formation of thehydrochloride salt to afford the title compound (0.068 g, 68%) as alight tan solid. MW=435.77. ¹H NMR (DMSO-d₆, 300 MHz) δ 14.23 (s, 1H),9.76 (s, 1H), 7.80-7.78 (m, 1H), 7.71-7.63 (m, 2H), 7.32 (d, J=8.4 Hz,2H), 7.26 (d, J=8.4 Hz, 2H), 6.87 (s, 1H), 4.66 (s, 1H), 3.63 (t, J=6.9Hz, 2H), 3.1 (t, J=7.6 Hz, 2H), 2.94 (t, J=7.6 Hz, 2H), 2.73 (t, J=6.9Hz, 2H), 2.30-2.14 (m, 2H); APCI MS m/z 399 [M+H]⁺.

EXAMPLE 1572-(4-((2-(3,5-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol)was reacted with (3,5-dichlorophenyl)boronic acid (0.396 g, 2.07 mmol),followed by the formation of the hydrochloride salt to afford the titlecompound (0.310 g, 100%) as a white solid. MW=335.06. ¹H NMR (CD₃OD, 300MHz) δ 14.06 (s, 1H), 8.02-7.93 (m, 2H), 7.71 (s, 1H), 7.50 (t, J=1.8Hz, 1H), 3.17-3.01 (m, 4H), 2.27-2.17 (m, 2H); APCI MS m/z 297 [M+H]⁺.

EXAMPLE 1572-(4-((2-(3,4-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure A1,4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with2-(4-aminophenyl)acetamide (0.060 g, 0.40 mmol), followed by theformation of the hydrochloride salt to afford the title compound (0.024g, 18%) as a tan solid. MW=448.77. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.12 (s,1H), 9.53 (s, 1H), 7.89 (d, J=2.0 Hz, 2H), 7.81 (s, 1H), 7.36 (s, 4H),7.13 (s, 1H), 3.73 (s, 2H), 3.63 (s, 2H), 3.11 (t, J=7.6 Hz, 2H), 2.91(t, J=7.6 Hz, 2H), 2.30-2.14 (m, 2H); APCI MS m/z 412 [M+H]⁺.

EXAMPLE 1582-(4-((2-(3,5-Dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure A1,4-chloro-2-(3,5-dichlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.100 g, 0.33 mmol) was reacted with 4-aminophenethylalcohol (0.055 g, 0.40 mmol), followed by the formation of thehydrochloride salt to afford the title compound (0.065 g, 65%) as alight yellow solid. MW=435.77. ¹H NMR (DMSO-d₆, 300 MHz) δ 14.15 (s,1H), 9.69 (s, 1H), 7.88 (d, J=1.8 Hz, 2H), 7.87-7.83 (m, 1H), 7.33 (s,4H), 7.07 (s, 1H), 3.64 (t, J=6.9, 2H), 3.13 (t, J=7.6 Hz, 2H), 2.92 (t,J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.28-2.17 (m, 2H); APCI MS m/z399 [M+H]⁺.

EXAMPLE 1592-(4-((2-(m-Tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride

Following General Procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.300 g, 1.60 mmol)was reacted with 3-tolyboronic acid (0.282 g, 2.07 mmol), followed bythe formation of the hydrochloride salt to afford the title compound(0.244 g, 82%) as a white solid. MW=280.19. ¹H NMR (CDCl₃, 500 MHz) δ13.97 (s, 1H), 7.97 (s, 1H), 7.91 (d, J=7.5 Hz, 1H), 7.74 (s, 1H), 7.49(t, J=7.5 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H), 3.84 (t, J=7.6 Hz, 2H), 3.15(t, J=7.6 Hz, 2H), 2.49 (s, 3H), 2.41-2.37 (m, 2H); APCI MS m/z 244[M+H]⁺.

EXAMPLE 1592-(4-((2-(m-Tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following General Procedure A2,4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride(0.075 g, 0.27 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.048g, 0.32 mmol), followed by the formation of the hydrochloride salt toafford the title compound (0.075 g, 99%) as a tan solid. MW=393.91. ¹HNMR (DMSO-d₆, 500 MHz) δ 13.93 (s, 1H), 9.79 (s, 1H), 7.57 (s, 1H), 7.51(d, J=7.5 Hz, 2H), 7.46 (t, J=7.5 Hz, 1H), 7.41 (d, J=7.5 Hz, 1H),7.39-7.33 (m, 4H), 6.96 (s, 1H), 6.91 (s, 1H), 3.42 (s, 2H), 3.16 (t,J=7.6 Hz, 2H), 2.92 (t, J=7.6 Hz, 2H), 2.39 (s, 3H), 2.24 (quin, J=7.6Hz, 2H); APCI MS m/z 358 [M+H]⁺.

EXAMPLE 1602-(4-((2-(m-Tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following General Procedure A2,4-chloro-2-(m-tolyl)-6,7-dihydro-5H-cyclopenta[b]pyridine hydrochloride(0.075 g, 0.27 mmol) was reacted with 4-aminophenethyl alcohol (0.044 g,0.32 mmol), followed by the formation of the hydrochloride salt toafford the title compound (0.078 g, 100%) as a brown solid. MW=380.91.¹H NMR (DMSO-d₆, 500 MHz) δ 13.88 (s, 1H), 9.75 (s, 1H), 7.56 (s, 1H),7.52-7.44 (m, 2H), 7.41 (d, J=7.5 Hz, 1H), 7.38-7.26 (m, 4H), 6.93 (s,1H), 3.64 (t, J=6.9, 2H), 3.59 (t, J=6.9 Hz, 1H), 3.15 (t, J=7.6 Hz,2H), 2.91 (t, J=7.6 Hz, 2H), 2.76 (t, J=6.9 Hz, 2H), 2.39 (m, 3H), 2.24(quin, J=7.6, 2H); APCI MS m/z 345 [M+H]⁺.

EXAMPLE 1612-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)aceticacid

Step 1. Preparation of ethyl2-(4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate

Following General Procedure B1,2-chloro-4-iodo-6-(trifluoromethyl)pyridine (0.244 g, 0.80 mmol) wasreacted with ethyl 2-(4-aminophenyl)acetate (0.156 g, 0.87 mmol) toafford the title compound (0.066 g, 33%) as a colorless oil. MW=358.74.¹H NMR (CDCl₃, 500 MHz) δ 7.37-7.31 (m, 2H), 7.17-7.12 (m, 2H), 7.00 (d,J=2.0 Hz, 1H), 6.87 (d, J=2.0 Hz, 1H), 6.43 (s, 1H), 4.19 (q, J=7.2 Hz,2H), 3.64 (s, 2H), 1.32-1.25 (m, 3H); APCI MS m/z 359 [M+H]⁺.

Step 2. Preparation of2-(4-((2-(cyclopent-1-en-1-yl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)aceticacid

Following General Procedure F, ethyl2-(4-((2-chloro-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)acetate(0.115 g, 0.32 mmol) was reacted with cyclopent-1-en-1-ylboronic acid(0.039 g, 0.35 mmol) to afford the title compound (0.028 g, 24%) as ayellow oil. MW=362.35. ¹H NMR (CDCl₃, 500 MHz) δ.7.35-7.28 (m, 2H),7.18-7.11 (m, 2H), 7.02-6.95 (m, 1H), 6.89 (s, 1H), 6.69-6.63 (m, 1H),6.18 (s, 1H), 3.65 (s, 3H), 2.05 (q, J=7.5 Hz, 4H), 1.30-1.22 (m, 2H);APCI MS m/z 363 [M+H]⁺.

EXAMPLE 1612-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)aceticacid

To a solution of2-(4-((2-(cyclopent-1-en-1-yl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)aceticacid (0.050 g, 0.14 mmol) in ethanol (5 mL) was added 10% Pd/C (0.002 g)and the mixture was stirred under an hydrogen atmosphere at rt for 48 h.After this time, the mixture was cooled and filtered through celite withethanol washing. The filtrate was dried over sodium sulfate, filtered,and concentrated. The residue was purified by column chromatography(silica, hexane/ethyl acetate) to afford the title compound (0.021 g,43%) as a light brown solid. MW=364.36. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.09(s, 1H), 7.27 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 7.03 (s, 1H),6.93 (s, 1H), 3.54 (s, 2H), 3.10-3.01 (m, 1H), 2.01-1.89 (m, 2H),1.81-1.57 (m, 6H), 1.24 (s, 1H); APCI MS m/z 365 [M+H]⁺.

EXAMPLE 1622-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)ethanol

Following general procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.208 g, 0.78 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.118 g,0.86 mmol) to afford the title compound (0.175 g, 61%) as a white solid.MW=365.86. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.78 (s, 1H), 8.28-8.22 (m, 2H),7.70 (d, J=8.5 Hz, 2H), 7.53-7.49 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.62(t, J=5.0 Hz, 1H), 3.65-3.59 (m, 2H), 2.29-2.84 (m, 4H), 2.72 (t, J=7.5Hz, 2H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 366 [M+H]⁺.

EXAMPLE 1633-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-1-ol

4-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.090 g, 0.40 mmol) and 3-(4-aminophenyl)propan-1-ol (0.060 g, 0.40mmol) were suspended in acetic acid (2 mL). The mixture was heated to120° C. for 1 h. After this time, the reaction was cooled, diluted withsaturated aqueous sodium bicarbonate, and extracted with ethyl acetate.The mixture was concentrated, redissolved in methanol (5 mL), andlithium hydroxide (4 equiv) was added. The mixture stirred for 1 h,diluted with water, and extracted with ethyl acetate. The combinedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, dichloromethane/ethyl acetate) to afford thetitle compound (0.061 g, 40%) as a white solid. MW=379.88. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.83 (s, 1H), 8.28-8.21 (m, 2H), 7.69 (d, J=8.5 Hz,2H), 7.54-7.49 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 3.44 (t, J=6.5 Hz, 1H),2.92-2.85 (m, 4H), 2.61 (t, J=7.5 Hz, 2H), 2.10 (quin, J=7.5 Hz, 2H),1.76-1.74 (m, 2H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 1641-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-one

Step 1. Preparation of 1-(4-aminophenyl)propan-2-one

To a solution of 1-(4-nitrophenyl)propan-2-one (0.650 g, 3.63 mmol) inethanol (20 mL) was added 10% palladium on carbon (0.060 g) and themixture stirred at rt under 1 atm of H₂ for 1 h. After this time, themixture was filtered over celite, concentrated, and the residue waspurified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.280 g, 51%) as an orange oil. MW=149.19. ¹HNMR (CDCl₃, 500 MHz) δ 7.00-6.96 (m, 2H), 6.68-6.63 (m, 2H), 3.63 (s,2H), 3.56 (s, 2H), 2.11 (s, 3H); APCI MS m/z 150 [M+H]⁺.

EXAMPLE 1641-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-one

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.140 g, 0.53 mmol) was reacted with 1-(4-aminophenyl)propan-2-one(0.094 g, 0.63 mmol) to afford the title compound (0.119 g, 60%) as alight yellow solid. MW=377.87. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.84 (s, 1H),8.29-8.22 (m, 2H), 7.75 (d, J=8.5 Hz, 2H), 7.55-7.48 (m, 2H), 7.20 (d,J=8.5 Hz, 2H), 3.74 (s, 2H), 2.94-2.84 (m, 4H), 2.15 (s, 3H), 2.14-2.06(m, 2H); APCI MS m/z 378 [M+H]⁺.

EXAMPLE 1651-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-ol

To a solution of1-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-one(0.072 g, 0.19 mmol) in methanol (5 mL) was added sodium borohydride(0.014 g, 0.38 mmol). The mixture stirred at rt for 10 min. After thistime, the mixture was diluted with a saturated solution of NaHCO₃ andextracted with ethyl acetate. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate) to afford the title compound (0.069 g, 95%) as a white solid.MW=379.88. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.27 (s, 1H), 8.29-8.16 (m, 2H),7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d, J=8.5 Hz, 2H), 4.54(d, J=5.0 Hz, 1H), 3.87-3.80 (m, 1H), 2.93-2.84 (m, 4H), 2.72-2.66 (m,1H), 2.58-2.53 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H), 1.06 (d, J=6.0 Hz,3H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 1662-(3-Chlorophenyl)-N-phenyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

Following general procedure A1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.185 g, 0.70 mmol) was reacted with aniline (0.130 g, 1.4 mmol) toafford the title compound (0.215 g, 95%) as an orange solid. MW=321.80.¹H NMR (DMSO-d₆, 500 MHz) δ 8.25 (s, 1H), 8.30-8.22 (m, 2H), 7.79 (d,J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.41-7.35 (m, 2H), 7.10-7.05 (m, 1H),2.93-2.86 (m, 4H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 322 [M+H]⁺.

EXAMPLE 1673-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propanamide

Following general procedure A1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.060 g, 0.23 mmol) was reacted with methyl3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.050 g, 0.23 mmol) to affordthe title compound (0.021 g, 23%) as a light brown solid. The intendedproduct (methyl3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-oxopropanoate)was very minor and not isolated. MW=392.88. ¹H NMR (DMSO-d₆, 500 MHz) δ8.78 (s, 1H), 8.30-8.21 (m, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.55-7.49 (m,2H), 7.29 (s, 1H), 7.21 (d, J=8.5 Hz, 2H), 6.75 (s, 1H), 2.94-2.84 (m,4H), 2.80 (t, J=7.5 Hz, 2H), 2.37 (t, J=7.5 Hz, 2H), 2.10 (quin, J=7.5Hz, 2H); APCI MS m/z 393 [M+H]⁺.

EXAMPLE 1682-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-hydroxypropanamide

Step 1. Preparation of isopropyl3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-oxopropanoate

Following general procedure A1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.063 g, 0.24 mmol) was reacted with isopropyl3-amino-2-(4-aminobenzyl)-3-oxopropanoate (0.060 g, 0.24 mmol) to affordthe title compound (0.090 g, 78%) as a light brown foam. MW=478.97. APCIMS m/z 479 [M+H]⁺.

EXAMPLE 1682-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-hydroxypropanamide

To a solution of isopropyl3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-oxopropanoate(0.090 g, 0.19 mmol) in THF (5 mL) was added lithium aluminum hydride(1.0 M, 0.38 mL, 0.38 mmol). The mixture stirred at 0° C. for 2 h. Themixture was quenched with water and sodium hydroxide (2M) and thenextracted with ethyl acetate. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.020 g, 25%) asa white solid. MW=422.91. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.77 (s, 1H),8.30-8.21 (m, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.23 (s,1H), 7.18 (d, J=8.0 Hz, 2H), 6.73 (s, 1H), 4.67 (t, J=5.5 Hz, 1H),3.59-3.52 (m, 1H), 3.43-3.36 (m, 1H), 2.94-2.84 (m, 4H), 2.79-2.56 (m,3H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 423 [M+H]⁺.

EXAMPLE 1692-(3-Chlorophenyl)-N-(4-(2-(dimethylamino)ethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-aminehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.093 g, 0.35 mmol) was reacted with 4-(2-(dimethylamino)ethyl)aniline(0.069 g, 0.42 mmol), followed by formation of the hydrochloride salt toafford the title compound (0.113 g, 75%) as a light yellow solid.MW=429.39. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.80 (s, 1H), 8.30-8.22 (m, 2H),7.72 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.24 (d, J=8.5 Hz, 2H),2.93-2.85 (m, 4H), 2.80-2.66 (m, 4H), 2.37 (s, 6H), 2.10 (quin, J=8.5Hz, 2H); APCI MS m/z 393 [M+H]⁺.

EXAMPLE 1702-(3-Chlorophenyl)-N-(4-(2-(dimethylamino)ethyl)phenyl)-6-ethylpyrimidin-4-aminehydrochloride

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.085 g, 0.33 mmol) wasreacted with 4-(2-(dimethylamino)ethyl)aniline (0.066 g, 0.40 mmol),followed by formation of the hydrochloride salt to afford the titlecompound (0.101 g, 72%) as a light yellow solid. MW=417.37. ¹H NMR(DMSO-d₆, 500 MHz) δ 9.60 (s, 1H), 8.35-8.27 (m, 2H), 7.66 (d, J=8.5 Hz,2H), 7.59-7.52 (m, 2H), 7.26 (d, J=8.5 Hz, 2H), 6.60 (s, 1H), 2.91-2.78(m, 4H), 2.67 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H); APCI MS m/z 381[M+H]⁺.

EXAMPLE 1712-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)acetamide

A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g,0.59 mmol) and 2-(4-aminophenyl)acetamide (0.107 g, 0.71 mmol) and 4MHCl in dioxane (2 drops) in acetic acid (3 mL) was heated for 2 h at108° C. After this time, the mixture was cooled to rt, neutralized withsaturated NaHCO₃, extracted with EtOAc, dried (Na₂SO₄), filtered, andconcentrated. The residue was purified by silica gel chromatographyeluting with methylene chloride and methanol to afford the titlecompound (0.135 g, 62%) as a white solid. MW=366.84. ¹H NMR (DMSO-d₆,500 MHz) δ 9.57 (s, 1H), 8.33-8.29 (m, 2H), 7.64 (d, J=8.4 Hz, 2H),7.58-7.54 (m, 2H), 7.43 (br s, 1H), 7.27 (d, J=8.5 Hz, 2H), 6.86 (br s,1H), 6.59 (s, 1H), 3.35 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6Hz, 3H); ESI MS m/z 367 [M+H]⁺.

EXAMPLE 172(R)-1-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-ol

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.075 g, 0.28 mmol) was reacted with (R)-1-(4-aminophenyl)propan-2-ol(0.050 g, 0.34 mmol) to afford the title compound (0.045 g, 42%) as alight yellow solid. MW=379.88. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.77 (s, 1H),8.29-8.23 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d,J=8.5 Hz, 2H), 4.54 (d, J=5.0 Hz, 1H), 3.88-3.80 (m, 1H), 2.93-2.84 (m,4H), 2.72-2.66 (m, 1H), 2.59-2.53 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H),1.06 (d, J=6.0 Hz, 3H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 173(S)-1-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)propan-2-ol

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.107 g, 0.40 mmol) was reacted with (S)-1-(4-aminophenyl)propan-2-ol(0.066 g, 0.44 mmol) to afford the title compound (0.123 g, 80%) as alight yellow solid. MW=379.88. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.77 (s, 1H),8.29-8.16 (m, 2H), 7.69 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.20 (d,J=8.5 Hz, 2H), 4.54 (d, J=5.0 Hz, 1H), 3.87-3.80 (m, 1H), 2.93-2.84 (m,4H), 2.72-2.66 (m, 1H), 2.58-2.53 (m, 1H), 2.10 (quin, J=7.5 Hz, 2H),1.06 (d, J=6.0 Hz, 3H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 1742-(3-Chlorophenyl)-N-(4-vinylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

Following general procedure B1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.200 g, 0.75 mmol) was reacted with 4-vinylaniline (0.098 g, 0.83mmol) to afford the title compound (0.160 g, 62%) as a light yellowsolid. MW=347.84. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.82 (s, 1H), 8.31-8.23(m, 2H), 7.81 (d, J=8.5 Hz, 2H), 7.55-7.47 (m, 4H), 6.77-6.68 (m, 1H),5.77 (d, J=17.5 Hz, 1H), 5.19 (d, J=11.0 Hz, 1H), 2.96-2.87 (m, 4H),2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 348 [M+H]⁺.

EXAMPLE 1751-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)ethane-1,2-diol

To a suspension of2-(3-chlorophenyl)-N-(4-vinylphenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine(0.098 g, 0.28 mmol) in acetone (10 mL) and water (5 mL) was added4-methylmorpholine N-oxide (0.183 g, 1.4 mmol) and potassium osmatedihydrate (0.002 g, 0.0056 mmol). The mixture was stirred at rt for 16h. After this time, the reaction mixture was absorbed onto silica andpurified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.063 g, 58%) as a light brown solid.MW=381.86. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.82 (s, 1H), 8.30-8.22 (m, 2H),7.74 (d, J=8.5 Hz, 2H), 7.54-7.49 (m, 2H), 7.33 (d, J=8.5 Hz, 2H), 5.16(d, J=4.5 Hz, 1H), 4.68 (t, J=6.0 Hz, 1H), 4.55-4.51 (m, 1H), 3.46 (t,J=6.0 Hz, 2H), 2.95-2.85 (m, 4H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z382 [M+H]⁺.

EXAMPLE 1763-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)-1,1,1-trifluoropropan-2-ol

Step 1. Preparation of2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetaldehyde

To a solution of2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)ethanol(0.175 g, 0.48 mmol) in methylene chloride (10 mL) was added Dess-Martinperiodinate (0.304 g, 0.72 mmol). The mixture stirred at rt for 16 h.After this time, the reaction was quenched with water and a saturatedsolution of Na₂S₂O₃ and then extracted with ethyl acetate. The organiclayer were dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the titlecompound (0.114 g, 65%) as an orange oil. MW=363.84. ¹H NMR (CDCl₃, 500MHz) δ 9.78 (t, J=2.3 Hz, 1H), 8.40-8.37 (m, 1H), 8.29-8.25 (m, 1H),7.71 (d, J=8.5 Hz, 2H), 7.41-7.36 (m, 2H), 7.27-7.23 (m, 2H), 6.33 (s,1H), 3.71 (d, J=2.3 Hz, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.81 (t, J=7.5 Hz,2H), 2.21 (quin, J=7.5 Hz, 2H); APCI MS m/z 364 [M+H]⁺.

EXAMPLE 1763-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)-1,1,1-trifluoropropan-2-ol

To a solution of2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetaldehyde(0.114 g, 0.31 mmol) in THF (10 mL) was addedtrimethyl(trifluoromethyl)silane (0.053 g, 0.38 mmol). The mixturestirred at 0° C. for 1 h after which tributylammonium fluoride (1.0 M,0.078 mL, 0.078 mmol) was added. The mixture stirred at rt for 16 h.After this time, the reaction was diluted with water and extracted withethyl acetate. The organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by preparative HPLC (water/acetonitrile with 0.05% TFA) toafford the title compound (0.010 g, 7%) as a light yellow solid.MW=433.85. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.82 (s, 1H), 8.30-8.22 (m, 2H),7.75 (d, J=8.5 Hz, 2H), 7.56-7.49 (m, 2H), 7.31 (d, J=8.5 Hz, 2H), 6.20(d, J=11.5 Hz, 1H), 4.23-4.12 (m, 1H), 2.95-2.85 (m, 4H), 2.76-2.68 (m,1H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 434 [M+H]⁺.

EXAMPLE 1772-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-2-methylphenyl)acetonitrile

Following procedure A2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.120 g, 0.47 mmol) was reacted with2-(4-amino-2-methylphenyl)acetonitrile (0.104 g, 0.71 mmol) to affordthe title compound (0.054 g, 45%) as an off-white solid. MW=374.87. ¹HNMR (DMSO-d₆, 500 MHz) δ 9.31 (s, 1H), 8.28 (s, 1H), 8.22 (d, J=7.0 Hz,1H), 7.79 (s, 1H), 7.63-7.54 (m, 3H), 7.36 (d, J=8.2 Hz, 1H), 3.99 (s,2H), 3.01-2.94 (m, 2H), 2.93-2.87 (m, 2H), 2.36 (s, 3H), 2.14 (t, J=7.6Hz, 2H); APCI MS m/z 375 [M+H]⁺.

EXAMPLE 1784-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)butanamide

A solution of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.032 g, 0.12 mmol), 4-aminobutanamide (0.061 g, 0.60 mmol), andN,N-diisopropylethylamine (0.031 g, 0.24 mmol) in NMP (3 mL) was heatedat 90° C. overnight. After this time, the reaction mixture was cooled,diluted water, and extracted with ethyl acetate. The combined organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated to afford the title compound (0.019 g, 61%) asa white solid. MW=330.81. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.31-8.26 (m, 2H),7.51-7.46 (m, 2H), 7.27 (s, 1H), 7.03 (t, J=5.5 Hz, 1H), 6.73 (s, 1H),3.48 (q, J=6.7 Hz, 2H), 2.81 (t, J=7.6 Hz, 2H), 2.68 (t, J=7.3 Hz, 2H),2.16 (t, J=7.6 Hz, 2H), 2.03 (quin, J=7.6 Hz, 2H), 1.84 (quin, J=7.3 Hz,2H); APCI MS m/z 331 [M+H]⁺.

EXAMPLE 1792-(3-Chlorophenyl)-N-(4-(oxazol-2-ylmethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

Step 1. Preparation of 2-(4-nitrobenzyl)oxazole

A mixture of 2-(4-nitrophenyl)acetamide (1.0 g, 5.55 mmol),1,3-dioxol-2-one (0.955 g, 11.10 mmol), and Eaton's Reagent (9.9 g,34.97 mmol) was heated to 100° C. overnight under a nitrogen atmosphere.After this time, the reaction was cooled, diluted with ice water, andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.250 g, 25%).MW=204.18. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.26-8.18 (m, 2H), 8.05 (d, J=0.8Hz, 1H), 7.57 (d, J=8.8 Hz, 2H), 7.16 (s, 1H), 4.34 (s, 2H); APCI MS m/z205 [M+H]⁺.

Step 2. Preparation of 4-(oxazol-2-ylmethyl)aniline

To a solution of 2-(4-nitrobenzyl)oxazole (0.108 g, 0.59 mmol) inethanol (3 mL) was added tin chloride (0.531 g, 2.35 mmol) and themixture was stirred at 50° C. for 3 h. After this time, the reactionmixture was cooled, diluted with 1M sodium hydroxide, and extracted withethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated to affordthe title compound (0.076 g, 63%) as a yellow oil. MW=174.20. ¹H NMR(CD₃OD, 500 MHz) δ 7.78 (d, J=0.8 Hz, 1H), 7.05 (d, J=0.8 Hz, 1H),7.02-6.97 (m, 2H), 6.69-6.65 (m, 2H), 3.97 (s, 2H); APCI MS m/z 175[M+H]⁺.

EXAMPLE 1792-(3-Chlorophenyl)-N-(4-(oxazol-2-ylmethyl)phenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

Following General Procedure B2,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.075 g, 0.28 mmol) was reacted with 4-(oxazol-2-ylmethyl)aniline(0.074 g, 0.42 mmol) to afford the title compound (0.043 g, 58%) as anoff-white solid. MW=402.88. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.88 (s, 1H),8.30-8.19 (m, 2H), 8.03 (d, J=0.8 Hz, 1H), 7.83-7.73 (m, 2H), 7.56-7.50(m, 2H), 7.28 (d, J=8.6 Hz, 2H), 7.15 (d, J=0.8 Hz, 1H), 4.13 (s, 2H),2.90 (q, J=7.6 Hz, 4H), 2.20-2.04 (m, 2H); APCI MS m/z 403 [M+H]⁺.

EXAMPLE 180(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)methanesulfonamide

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.075 g, 0.28 mmol) was reacted with (4-aminophenyl)methanesulfonamide(0.058 g, 0.31 mmol) to afford the title compound (0.043 g, 58%) as awhite solid. MW=414.91. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.93 (s, 1H),8.32-8.21 (m, 2H), 7.85 (d, J=8.6 Hz, 2H), 7.57-7.50 (m, 2H), 7.36 (d,J=8.6 Hz, 2H), 6.85 (s, 2H), 4.25 (s, 2H), 2.99-2.86 (m, 4H), 2.18-2.05(m, 2H); APCI MS m/z 415 [M+H]⁺.

EXAMPLE 1812-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetamide

Step 1. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate

A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.200 g,0.79 mmol), methyl 2-(4-hydroxyphenyl)acetate (0.131 g, 0.79 mmol) andpotassium carbonate (0.546 g, 3.95 mmol) in acetonitrile (5 mL) washeated to 85° C. for 7 h. The reaction mixture was diluted with waterand extracted with ethyl acetate. The combined organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/dichloromethane) to afford the title compound (0.130 g, 65%).MW=382.84. ¹H NMR (CD₃OD, 500 MHz) δ 8.21 (t, J=1.8 Hz, 1H), 8.16-8.12(m, 1H), 7.46-7.35 (m, 4H), 7.21-7.17 (m, 2H), 6.77 (s, 1H), 3.73 (s,2H), 3.72 (s, 3H), 2.83 (q, J=7.6 Hz, 2H), 1.35 (t, J=6.4 Hz, 3H); APCIMS m/z 383 [M+H]⁺.

EXAMPLE 1812-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetamide

Methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate(0.075 g, 0.20 mmol) and ammonia in methanol (7 M, 3 mL) were heated at100° C. for 72 h. After this time, the crude reaction solution wascooled, evaporated, and purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.048 g, 64%) asa white solid. MW=367.83. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.16-8.13 (m, 1H),8.14-8.11 (m, 1H), 7.59-7.55 (m, 1H), 7.51 (t, J=7.9 Hz, 2H), 7.39-7.36(m, 2H), 7.24-7.21 (m, 2H), 6.92 (s, 1H), 6.90 (s, 1H), 3.44 (s, 2H),2.80 (q, J=7.6 Hz, 2H), 1.28 (t, J=7.6 Hz, 3H); APCI MS m/z 368 [M+H]⁺.

EXAMPLE 1822-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)ethanol

To a solution of methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)phenyl)acetate(0.075 g, 0.20 mmol) in THF (1.3 mL) at 0° C. was added BH₃.SMe₂ (0.031g, 0.39 mmol). The mixture was warmed to rt and stirred overnight. Afterthis time, the reaction was quenched with 0.5M HCl, diluted withsaturated aqueous sodium bicarbonate, and extracted with ethyl acetate.The combined organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, methanol/dichloromethane) to afford thetitle compound as a white solid (0.052 g, 69%). MW=354.83. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.17-8.10 (m, 2H), 7.59-7.54 (m, 1H), 7.51 (t,J=7.9 Hz, 1H), 7.37-7.32 (m, 2H), 7.22-7.17 (m, 2H), 6.88 (s, 1H), 4.67(t, J=5.2 Hz, 1H), 3.68-3.62 (m, 2H), 2.79 (q, J=7.3 Hz, 4H), 1.28 (t,J=7.6 Hz, 3H); APCI MS m/z 355 [M+H]⁺.

EXAMPLE 1832-(6-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)pyridin-3-yl)acetamide

Step 1. Preparation of (6-methoxypyridin-3-yl)methanol

A solution of methyl 2-methoxypyridine-5-carboxylate (8.4 g, 50 mmol) indioxane (70 mL) was treated with sodium borohydride (8.1 g, 244 mmol) at0° C. The reaction mixture was warmed to 100° C. and heating continuedovernight. After this time, the mixture was cooled, diluted withmethanol, filtered through a fritted funnel with methanol washes, andthe filtrate was concentrated. The residue was redissolved in water, 0.5M sodium hydroxide was added dropwise, and the mixture extracted withethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by column chromatography (silica, dichloromethane/methanol)to afford the title compound (2.9 g, 35%) as a colorless oil. MW=139.15.¹H NMR (CD₃OD, 300 MHz) δ 8.11-8.05 (m, 1H), 7.67 (dd, J₁=10.9 Hz,J₂=2.43 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 4.89 (s, 1H), 4.54 (s, 2H),3.89 (s, 3H); APCI MS m/z 140 [M+H]⁺.

Step 2. Preparation of (6-methoxypyridin-3-yl)methyl methanesulfonate

A solution of (6-methoxypyridin-3-yl)methanol (2.9 g, 20.93 mmol) andtriethylamine (4.35 mL) in dichloromethane (20 mL) was treated withmethanesulfonyl chloride (2.9 g, 25.1 mmol) dropwise and the reactionmixture stirred at rt overnight. After this time, the reaction wasdiluted with water and extracted with methylene chloride. The combinedorganic layer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated to afford the title compound (1.4 g, 49%) as ayellow oil. MW=217.24. ¹H NMR (CDCl₃, 300 MHz) δ 8.16-8.14 (m, 1H),7.68-7.59 (m, 1H), 6.76 (d, J=8.6 Hz, 1H), 4.55 (s, 2H), 3.94 (s, 3H),3.19 (s, 3H).

Step 3. Preparation of 2-(6-methoxy-1,6-dihydropyridin-3-yl)acetonitrile

A solution of (6-methoxypyridin-3-yl)methyl methanesulfonate (1.4 g,6.14 mmol) in acetonitrile (13 mL) was treated with sodium cyanide(0.752 g, 15.3 mmol) dropwise and the reaction mixture was heated atreflux for 48 h. After this time, the reaction was cooled andconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate) to afford the title compound (0.800 g, 57%) as awhite solid. MW=150.18. ¹H NMR (CD₃OD, 300 MHz) δ 8.12-8.09 (m, 1H),7.68 (dd, J₁=10.9 Hz, J₂=2.4 Hz, 1H), 6.82 (d, J=8.6 Hz, 1H), 4.86 (s,1H), 3.90 (s, 3H), 3.85 (s, 2H); APCI MS m/z 151 [M+H]⁺.

Step 4. Preparation of 2-(6-oxo-1,6-dihydropyridin-3-yl)acetonitrile

A solution of 2-(6-methoxy-1,6-dihydropyridin-3-yl)acetonitrile (0.400g, 2.7 mmol) and hydrogen bromide (4.1 g, 50.25 mmol) in ethanol (5 mL)was refluxed for 4 h. After this time, the reaction was cooled, dilutedwith saturated aqueous sodium bicarbonate, and extracted with ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.357 g, 89%) as a tan solid. MW=134.14. ¹HNMR (DMSO-d₆, 300 MHz) δ 11.70 (s, 1H), 7.42-7.34 (m, 2H), 6.31 (d, J=9Hz, 1H), 3.74 (s, 2H); APCI MS m/z 135 [M+H]⁺.

Step 5. Preparation of2-(6-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)pyridin-3-yl)acetonitrile

A solution of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.300 g,1.19 mmol), 2-(6-oxo-1,6-dihydropyridin-3-yl)acetonitrile (0.239 g, 1.78mmol), and potassium carbonate (0.246 g, 1.78 mmol) in DMF (3 mL) washeated with microwave irradiation to 120° C. for 1 h. After this time,the reaction was cooled and concentrated. The residue was purified bypreparative HPLC (water/acetonitrile with 0.05% TFA) to afford the titlecompound (0.066 g, 22%). MW=350.80. ¹H NMR (CD₃OD, 300 MHz) δ 8.51-8.41(m, 2H), 8.32-8.28 (m, 1H), 7.89 (s, 1H), 7.64 (dd, J_(I)=12.1 Hz,J₂=2.6 Hz, 1H), 7.56-7.47 (m, 2H), 6.70 (d, J=9.5 Hz, 1H), 3.87-3.82 (m,2H), 2.98 (q, J=7.6 Hz, 2H), 1.46-1.8 (m, 3H); APCI MS m/z 351 [M+H]⁺.

EXAMPLE 1832-(6-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)pyridin-3-yl)acetamide

Sulfuric acid (2 mL) was added to2-(6-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)oxy)pyridin-3-yl)acetonitrile(0.061 g, 0.18 mmol) at 0° C. and slowly warmed to rt. The mixture wasstirred for 2 h, diluted with saturated aqueous sodium bicarbonate, andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.020 g, 34%) asa white solid. MW=368.22. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.44-8.37 (m, 2H),8.10-8.05 (m, 1H), 7.92 (s, 1H), 7.70-7.56 (m, 2H), 7.53-7.43 (m, 2H),7.01 (s, 1H), 6.55 (d, J=9.4 Hz, 1H), 3.30 (d, 2H), 2.93 (q, J=7.6 Hz,2H), 1.33 (t, J=7.6 Hz, 3H); APCI MS m/z 369 [M+H]⁺.

EXAMPLE 1842-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropan-1-ol

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.075 g, 0.29 mmol) inNMP (3 mL) was reacted with 2-(4-aminophenyl)-2-methylpropan-1-ol (0.054g, 0.33 mmol) to afford the title compound (0.066 g, 88%) as a lightyellow solid. MW=381.91. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.54 (s, 1H),8.35-8.28 (m, 2H), 7.63 (d, J=8.6 Hz, 2H), 7.58-7.55 (m, 2H), 7.42-7.32(m, 2H), 6.59 (s, 1H), 4.64 (t, J=5.4 Hz, 1H), 3.42 (d, J=5.4 Hz, 2H),2.66 (q, J=7.6 Hz, 2H), 1.32-1.18 (m, 9H); APCI MS m/z 382 [M+H]⁺.

EXAMPLE 185 Ethyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)acetate

Step 1. Preparation of ethyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropanoate

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.055 g, 0.22 mmol) wasreacted with ethyl 2-(4-aminophenyl)-3,3,3-trifluoropropanoate (0.080 g,0.33 mmol) to afford the title compound (0.100 g, 100%) as an amber oil.MW=463.88. H NMR (CDCl₃, 300 MHz) δ 8.44-8.39 (m, 1H), 8.34-8.27 (m,1H), 7.57-7.46 (m, 4H), 7.44-7.36 (m, 2H), 6.87 (s, 1H), 6.54 (s, 1H),4.38-4.11 (m, 3H), 2.74 (q, J=7.6 Hz, 2H), 1.40-1.21 (m, 6H); APCI MSm/z 464 [M+H]⁺.

EXAMPLE 185 Ethyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)acetate

To a solution of ethyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropanoate(0.130 g, 0.28 mmol) in dioxane (11 mL) and water (7 mL) was addedLiOH.H₂O (0.035 g, 0.84 mmol) and the mixture was stirred at rt for 12h. After this time, the mixture was diluted with water and extractedwith ethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.053 g, 53%) as a white solid. MW=395.88. ¹HNMR (DMSO-d₆, 500 MHz) δ 9.60 (s, 1H), 8.34-8.27 (m, 2H), 7.67 (d, J=8.5Hz, 2H), 7.59-7.52 (m, 2H), 7.27 (d, J=8.5 Hz, 2H), 6.60 (s, 1H), 4.09(q, J=7.1 Hz, 2H), 3.64 (s, 2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6Hz, 3H), 1.20 (t, J=7.1 Hz, 3H); APCI MS m/z 396 [M+H]⁺.

EXAMPLE 1862-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropan-1-ol

A solution of ethyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-3,3,3-trifluoropropanoate(0.070 g, 0.15 mmol) in dichloromethane (3 mL) at 0° C. was slowlytreated with DIBAL (0.064 g, 0.45 mmol) dropwise and the resultingmixture was stirred for 2 h and then warmed to rt for 2 h. After thistime, the reaction was quenched with methanol, 2M HCl, and water andthen extracted with ethyl acetate. The combined organic layer was driedover anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate) to afford the title compound (0.035 g, 51%) as awhite solid. MW=421.84. ¹H NMR (DMSO-d₆, 300 MHz) δ 9.71 (s, 1H),8.38-8.27 (m, 2H), 7.75 (d, J=8.4 Hz, 2H), 7.61-7.52 (m, 2H), 7.39 (d,J=8.4 Hz, 2H), 6.63 (s, 1H), 5.10 (t, J=5.4 Hz, 1H), 4.02-3.91 (m, 1H),3.90-3.80 (m, 1H), 3.77-3.61 (m, 1H), 2.69 (q, J=7.6 Hz, 2H), 1.27 (t,J=7.6 Hz, 3H); APCI MS m/z 422 [M+H]⁺.

EXAMPLE 1872-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanamide

Step 1. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanoate

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.075 g, 0.29 mmol) inNMP (3 mL) was reacted with 2-(4-aminophenyl)-2-methylpropanamide (0.069g, 0.36 mmol) to afford the title compound (0.105 g, 100%) as an amberoil. MW=409.91. ¹H NMR (CDCl₃, 300 MHz) δ 8.44-8.39 (m, 1H), 8.33-8.26(m, 1H), 7.43-7.40 (m, 1H), 7.40-7.35 (m, 4H), 6.77 (s, 1H), 6.52 (s,1H), 4.12 (q, J=7.1 Hz, 1H), 3.69 (s, 3H), 2.71 (q, J=7.6 Hz, 2H), 2.61(s, 6H), 1.59 (s, 3H); APCI MS m/z 410 [M+H]⁺.

Step 2. Preparation of2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanoicacid

To a solution of methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanoate(0.100 g, 0.24 mmol) in dioxane (9 mL) and water (6 mL) was addedLiOH.H₂O (0.031 g, 0.73 mmol) and the reaction mixture stirred under anitrogen atmosphere at 50° C. for 16 h. After this time, the reactionmixture was cooled and treated with 1M HCl to pH 3.0 and concentrated toafford the title compound (0.167 g, 100%) as a yellow oil. MW=395.88. ¹HNMR (CDCl₃, 300 MHz) δ 9.79 (s, 1H), 8.86 (s, 1H), 8.44-8.39 (m, 1H),8.33-8.26 (m, 1H), 7.43-7.40 (m, 1H), 7.40-7.35 (m, 4H), 6.77 (s, 1H),6.52 (s, 1H), 2.89 (q, J=7.6 Hz, 2H), 2.42-2.38 (m, 3H), 2.08-2.00 (m,3H), 1.65-1.57 (m, 3H); APCI MS m/z 396 [M+H]⁺.

EXAMPLE 1872-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanamide

A suspension of2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)-2-methylpropanoicacid (0.150 g, 0.38 mmol) in methylene chloride (5 mL) and dioxane (5mL) under a nitrogen atmosphere was treated with oxalyl chloride (0.241g, 1.89 mmol), followed by the addition of DMF (1 drop). The reactionmixture was stirred at rt for 4 h. After this time, the mixture wasconcentrated and the residue was treated with ammonia (7.0 N inmethanol, 4 mL). The reaction mixture was stirred for 2 h, thenconcentrated and the residue was purified by preparative HPLC(water/acetonitrile with 0.05% TFA) to afford the title compound (0.065g, 44%) as a white solid. MW=394.90. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.60(s, 1H), 8.35-8.27 (m, 2H), 7.68 (d, J=9.0 Hz, 2H), 7.59-7.54 (m, 2H),7.37-7.32 (m, 2H), 6.86 (d, J=9.0 Hz, 2H), 6.60 (s, 1H), 2.67 (q, J=7.6Hz, 2H), 1.45 (s, 6H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 395 [M+H]⁺.

EXAMPLE 188N-(4-((4-chloro-1H-pyrazol-1-yl)methyl)phenyl)-2-(3-chlorophenyl)-6-ethylpyrimidin-4-amine

Step 1. Preparation of 4-chloro-1-(4-nitrobenzyl)-1H-pyrazole

A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.458 g,2.12 mmol), 4-chloro-1H-pyrazole (0.500 g, 4.88 mmol), and potassiumcarbonate (0.645 g, 4.67 mmol) in acetonitrile (27 mL) was stirred at rtovernight. After this time, the mixture was diluted with water andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated toafford the title compound (0.759 g, crude) as a white solid. MW=237.64.¹H NMR (CDCl₃, 500 MHz) δ 8.24-8.19 (m, 2H), 7.51 (s, 1H), 7.44 (s, 1H)7.36-7.31 (m, 2H), 5.36 (s, 2H); APCI MS m/z 238 [M+H]⁺.

Step 2. 4-((4-chloro-1H-pyrazol-1-yl)methyl)aniline

To a solution of 4-chloro-1-(4-nitrobenzyl)-1H-pyrazole (0.750 g, 3.16mmol) in ethyl acetate (30 mL) was added Pt/C (0.038 g, 0.19 mmol). Themixture was stirred at rt for 48 h, filtered through celite, washed withethyl acetate, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.357 g, 43%) as a peach solid. MW=207.66. ¹HNMR (CDCl₃, 500 MHz) δ 7.41 (s, 1H), 7.26 (s, 1H), 7.07-7.01 (m, 2H),6.65-6.59 (m, 2H), 5.09 (s, 2H), 3.74 (s, 2H); APCI MS m/z 207 [M+H]⁺.

EXAMPLE 188N-(4-((4-Chloro-1H-pyrazol-1-yl)methyl)phenyl)-2-(3-chlorophenyl)-6-ethylpyrimidin-4-amine

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g, 0.39 mmol) inNMP (3 mL) was reacted with 4-((4-chloro-1H-pyrazol-1-yl)methyl)aniline(0.098 g, 0.47 mmol) to afford the title compound (0.078 g, 78%) as alight brown solid. MW=424.33. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.67 (s, 1H),8.34-8.26 (m, 2H), 8.09 (s, 1H), 7.71 (d, J=8.5 Hz, 2H), 7.60-7.52 (m,3H), 7.32-7.27 (m, 2H), 6.61 (s, 1H), 5.26 (s, 2H), 2.67 (q, J=7.6 Hz,2H), 1.29-1.24 (m, 3H); APCI MS m/z 424 [M+H]⁺.

EXAMPLE 189N-(4-((1H-Pyrazol-1-yl)methyl)phenyl)-2-(3-chlorophenyl)-6-ethylpyrimidin-4-amine

Step 1. Preparation of 1-(4-nitrobenzyl)-1H-pyrazole

A mixture of 4-nitrobenzyl bromide (0.500 g, 2.31 mmol), 1H-pyrazole(0.362 g, 5.23 mmol), and potassium carbonate (0.704 g, 5.09 mmol) inacetonitrile (30 mL) was stirred at rt overnight. After this time, themixture was diluted with water and extracted with ethyl acetate. Thecombined organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.380 g, 76%) as a white solid. MW=203.20. ¹H NMR(CDCl₃, 500 MHz) δ 8.21-8.19 (m, 1H), 8.19-8.16 (m, 1H), 7.61-7.57 (m,1H), 7.48-7.44 (m, 1H), 7.32-7.28 (m, 2H), 6.35 (t, J=2.1 Hz, 1H), 5.44(s, 2H); APCI MS m/z 204 [M+H]⁺.

Step 2. Preparation of 4-((1H-pyrazol-1-yl)methyl)aniline

A solution of 1-(4-nitrobenzyl)-1H-pyrazole (0.375 g, 1.85 mmol) inethyl acetate (15 mL) was treated with Pt/C (0.018 g, 0.09 mmol) and themixture stirred at rt for 16 h under a hydrogen atmosphere. After thistime, the mixture was filtered through celite, washed with ethylacetate, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.213 g, 57%) as a yellow solid. MW=173.21. ¹H NMR(CDCl₃, 300 MHz) δ 7.58-7.47 (m, 1H), 7.32 (d, J=2.1 Hz, 1H), 7.09-7.01(m, 2H), 6.68-6.59 (m, 2H), 6.24 (t, J=2.1 Hz, 1H), 5.19 (s, 2H), 3.69(s, 2H); APCI MS m/z 174 [M+H]⁺.

EXAMPLE 189N-(4-((1H-Pyrazol-1-yl)methyl)phenyl)-2-(3-chlorophenyl)-6-ethylpyrimidin-4-amine

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g, 0.39 mmol) wasreacted with 4-((1H-pyrazol-1-yl)methyl)aniline (0.082 g, 0.47 mmol) toafford the title compound (0.067 g, 67%) as a yellow solid. MW=389.88.¹H NMR (DMSO-d₆, 500 MHz) δ 9.64 (s, 1H), 8.35-8.25 (m, 2H), 7.82 (d,J=2.1 Hz, 1H), 7.69 (d, J=8.4 Hz, 2H), 7.59-7.52 (m, 2H), 7.48-7.44 (m,1H), 7.30-7.23 (m, 2H), 6.00 (s, 1H), 6.27 (t, J=2.1 Hz, 1H), 5.30 (s,2H), 2.67 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); APCI MS m/z 390[M+H]⁺.

EXAMPLE 1904-(4-((4-Chloro-1H-pyrazol-1-yl)methyl)benzyl)-2-(3-chlorophenyl)-6-ethylpyrimidine

Step 1. Preparation of(4-((4-chloro-1H-pyrazol-1-yl)methyl)phenyl)methanol

A mixture of 4-(chloromethyl) benzyl alcohol (0.500 g, 3.19 mmol),4-chloro-1H-pyrazole (0.753 g, 7.34 mmol), and potassium carbonate(0.908 g, 7.02 mmol) in acetonitrile (40 mL) was stirred at rtovernight. After this time, the mixture was diluted with water andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate, filtered and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate) to afford the title compound (0.375 g, 75%) as a white solid.MW=222.67. ¹H NMR (CDCl₃, 500 MHz) δ 7.45 (s, 1H), 7.37 (s, 1H), 7.35(s, 1H), 7.33 (s, 1H), 7.23 (s, 1H), 7.22 (s, 1H), 5.24 (s, 2H), 4.70(d, J=5.9 Hz, 2H), 1.68 (t, J=5.9 Hz, 1H).

Step 2. Preparation of 1-(4-(bromomethyl)benzyl)-4-chloro-1H-pyrazole

A solution of (4-((4-chloro-1H-pyrazol-1-yl)methyl)phenyl)methanol(0.375 g, 1.68 mmol) in methylene chloride (7 mL) at 0° C. under anitrogen atmosphere was treated with PBr₃ (0.456 g, 1.68 mmol) and themixture was warmed to rt and stirred for 1 h. After this time, themixture was diluted with saturated aqueous sodium bicarbonate and iceand then extracted with dichloromethane. The combined organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/dichloromethane) to afford the title compound (0.342 g, 91%) asa white solid. MW=285.57. ¹H NMR (CDCl₃, 500 MHz) δ 7.46 (s, 1H), 7.38(d, J=8.1 Hz, 2H), 7.35 (s, 1H), 7.19 (d, J=8.1 Hz, 2H), 5.24 (s, 2H),4.47 (s, 2H).

Step 3. Preparation of4-chloro-1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-1H-pyrazole

A mixture of 1-(4-(bromomethyl)benzyl)-4-chloro-1H-pyrazole (0.340 g,1.19 mmol), pinacol diborane (0.363 g, 1.43 mmol),tetrakis(triphenylphosphine)palladium(0) (0.137 g, 0.12 mmol) and K₂CO₃(0.793 g, 3.57 mmol) in dioxane (10 mL) was stirred under an argonatmosphere at 80° C. for 18 h. After this time, the mixture was cooled,diluted with ethyl acetate (40 mL), and filtered through celite. Thefiltrate was washed with saturated sodium chloride (3×5 mL), dried oversodium sulfate, filtered, and concentrated. The residue was purified bycolumn chromatography (silica, hexanes/dichloromethane) to afford thetitle compound (0.240 g, crude) as a dark yellow oil. MW=332.63. ¹H NMR(CDCl₃, 500 MHz) δ 10.01 (s, 1H), 7.89-7.84 (m, 2H), 7.49 (s, 1H),7.46-7.43 (m, 1H), 7.41 (s, 1H), 7.36-7.29 (m, 3H), 7.19-7.06 (m, 3H),5.33 (s, 2H), 5.21-5.18 (m, 2H), 2.89 (s, 1H), 1.61 (s, 2H), 1.23 (s,3H).

EXAMPLE 1904-(4-((4-Chloro-1H-pyrazol-1-yl)methyl)benzyl)-2-(3-chlorophenyl)-6-ethylpyrimidine

A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.100 g,0.40 mmol),4-chloro-1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-1H-pyrazole(0.197 g, 0.59 mmol), Pd(dppf)Cl₂ (0.032 g, 0.04 mmol), and powderedNa₂CO₃ (0.126 g, 1.19 mmol) in dioxane (2.4 mL) and water (1.6 mL) wasstirred under an argon atmosphere at 90° C. for 6 h, cooled, andfiltered through celite with ethyl acetate washing. The filtrate waswashed with saturated sodium chloride (3×25 mL), dried over anhydroussodium sulfate, filtered, and concentrated. The residue was purified bycolumn chromatography (silica, hexane/dichloromethane) to afford thetitle compound (0.043 g, 43%) as a yellow oil. MW=423.34. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.38-8.32 (m, 2H), 8.05 (s, 1H), 7.62-7.50 (m, 3H),7.35 (d, J=8.1 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.1 Hz, 2H), 5.25 (s,2H), 4.11 (s, 2H), 2.77 (q, J=7.6 Hz, 2H), 1.26 (t, J=7.6 Hz, 3H); APCIMS m/z 423 [M+H]⁺.

EXAMPLE 1912-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)phenyl)ethanol

A mixture of 4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g,0.59 mmol) and 2-(4-aminophenyl)ethanol (0.134 g, 0.89 mmol) and 4M HClin dioxane (0.222 mL, 0.89 mmol) in EtOH was heated for 2.5 h at 85° C.After this time, the mixture was neutralized with NaHCO₃ at 0° C. andpurified by silica gel chromatography eluting with methylene chlorideand methanol to afford the title compound (0.145 g, 70%) as a yellowsolid. MW=353.85. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.53 (s, 1H), 8.33-8.28(m, 2H), 7.62-7.55 (m, 4H), 7.22 (d, J=8.4 Hz, 2H), 6.58 (s, 1H), 4.62(t, J=5.2 Hz, 1H), 3.63-3.59 (m, 2H), 2.72-2.64 (m, 4H), 1.26 (t, J=7.6Hz, 3H); ESI MS m/z 354 [M+H]⁺.

EXAMPLE 1922-(2-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)imino)-2,3-dihydrooxazol-5-yl)acetamide

Step 1. Preparation of methyl 4-oxobutanoate

A 500-mL Parr bottle was charged with methyl 4-chloro-4-oxobutyrate(20.0 g, 133 mmol), 2,6-lutidine (15.6 mL, 134 mmol) and 10% palladiumon carbon (1.4 g) in tetrahydrofuran (250 mL). This mixture wasvigorously shaken under H₂ (40 psi) for 6 h. The mixture was thenfiltered through celite and the filtrate concentrated under reducedpressure. The residue was distilled under vacuum (130° C./10 mm) toafford the title compound (8.52 g, 55%) as a colorless oil. MW=116.12.¹H NMR (CDCl₃, 300 MHz) δ 9.82 (s, 1H), 3.70 (s, 3H), 2.81 (t, J=6.6 Hz,2H), 2.64 (t, J=6.3 Hz, 2H).

Step 2. Preparation of methyl 3-bromo-4-oxobutanoate

A 500-mL round bottom flask was charged with methyl 4-oxobutanoate (8.52g, 73.3 mmol), dioxane (0.7 mL) in diethyl ether (70 mL). Bromine (3.94mL, 77.0 mmol) was added at room temperature over 1.5 h. After thistime, the mixture was diluted with dichloromethane (250 mL) and solidsodium bicarbonate (13.6 g, 161 mmol) was added. After stirring for 2 hthe mixture was filtered and the filtrate concentrated under reducedpressure to afford the title compound (15.3 g, 100%) as a colorless oil.MW=195.01. ¹H NMR (CDCl₃, 300 MHz) δ 9.54 (s, 1H), 4.68 (dd, J=6.9, 6.6Hz, 1H), 3.74 (s, 3H), 3.25 (dd, J=17.4, 7.2 Hz, 1H), 2.94 (dd, J=17.1,6.6 Hz, 1H).

Step 3. Preparation of methyl 2-(2-aminooxazol-5-yl)acetate

A 250-mL round bottom flask was charged with methyl3-bromo-4-oxobutanoate (5.00 g, 25.6 mmol) and urea (2.08 g, 34.6 mmol)in DMF (15 mL) and heated to 110° C. for 30 minutes. After this time,the mixture was cooled to room temperature and concentrated underreduced pressure. The residue was absorbed onto silica and purified bychromatography on silica using dichloromethane/(89:9:1dichloromethane/methane/conc. NH₄OH) (10:0 to 0:10) as eluent, to affordthe title compound (0.72 g, 18%) as a red oil. MW=156.14. ¹H NMR(DMSO-d₆, 300 MHz) δ 9.54 (s, 1H), 6.48 (s, 2H), 6.45 (s, 1H), 3.64 (s,2H), 3.62 (s, 3H).

Step 4. Methyl2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)oxazol-5-yl)acetate

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.150 g, 0.59 mmol),methyl 2-(2-aminooxazol-5-yl)acetate (0.138 g, 0.89 mmol), palladiumacetate (0.006 g, 0.029 mmol), rac-BINAP (0.028 g, 0.044 mmol) andcesium carbonate (0.482 g, 1.48 mmol) in dioxane (5 mL) under argon. Thereaction mixture was heated to 120° C. under microwave irradiation for 2h until the starting material was consumed (monitored by LCMS analysis).The reaction mixture was cooled and filtered through celite. Thefiltrate was diluted with ethyl acetate (50 mL), washed with saturatedsodium bicarbonate (10 mL), dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated under reduced pressure. Theresidue was purified by chromatography on silica using hexanes/ethylacetate (10:0 to 0:10) to afford the title compound (0.075 g, 34%) as anoff-white solid. MW=372.81. ¹H NMR (CDCl₃, 300 MHz) δ 8.65 (s, 1H),8.37-8.33 (m, 1H), 8.25 (dt, J=7.2, 1.5 Hz, 1H), 8.02 (s, 1H), 7.49-7.38(m, 2H), 6.40-6.35 (m, 1H), 4.08 (s, 2H), 3.41 (s, 3H), 2.91 (q, J=7.5Hz, 2H), 1.41 (t, J=7.5 Hz, 3H); ESI MS m/z 373 [M+H]⁺.

EXAMPLE 1922-(2-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)imino)-2,3-dihydrooxazol-5-yl)acetamide

A 20-mL vial was charged with methyl2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)amino)oxazol-5-yl)acetate(0.073 g, 0.20 mmol) and ammonium chloride (0.031 g, 0.59 mmol). To thiswas added methanol (4 mL) followed by NH₃ (5.6 mL, 7N in methanol, 39mmol). The vial was sealed and the resulting mixture was stirred at 100°C. for 65 h. The crude reaction solution concentrated under reducedpressure. The residue was adsorbed onto silica then purified bychromatography on silica using dichloromethane/methanol (10:0 to 8:2) aseluent to afford2-(2-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)imino)-2,3-dihydrooxazol-5-yl)acetamide(0.051 g, 72%) as an off-white solid. MW=357.79. M.p.>260° C. ¹H NMR(DMSO-d₆, 300 MHz) δ 8.68 (s, 1H), 8.61 (s, 1H), 8.37-8.32 (m, 2H), 8.00(s, 1H), 7.63-7.52 (m, 2H), 5.34 (d, J=8.1 Hz, 1H), 5.19 (ddd, J=8.1,8.1, 3.3 Hz, 1H), 2.99 (dd, J=18.0, 8.4 Hz, 1H), 2.76 (q, J=7.5 Hz, 2H),2.44 (dd, J=18.3, 3.6 Hz, 1H), 1.27 (t, J=7.5 Hz, 3H); APCI MS m/z 358[M+H]⁺.

EXAMPLE 1932-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-N-propylacetamide

Step 1. Preparation of2-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetylchloride

An 250-mL round bottom flask was charged with2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)aceticacid (0.22 g, 0.60 mmol) in dichloromethane (15 ml). To this solution at0° C. was added oxalyl chloride (0.25 mL, 3.00 mmol) followed by DMF (1drop). After stirring for 4 h, the volatile material was removed underreduced pressure to afford crude acid chloride as a red oil. MW=385.29.

EXAMPLE 1932-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-N-propylacetamide

To a stirred solution of crude2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetylchloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was addedn-propylamine (0.082 mL, 1.00 mmol) followed by diisopropylethylamine(0.17 mL, 1.00 mmol). After stirring for 2.5 h, the reaction mixture wasdiluted with dichloromethane (50 mL) and water (5 mL). The mixture wasacidified with 2N aqueous HCl until pH ˜5. The organic layer was washedwith saturated sodium chloride (5 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography on silica using hexanes/ethyl acetate (10:0to 1:1) as eluent followed by preparative HPLC (water/acetonitrile with0.05% TFA) to afford the title compound (0.044 g, 55%) as a white solid.MW=407.94. M.p. 123-125° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.37-8.31 (m,2H), 7.98-7.93 (m, 1H), 7.60 (dt, J=8.5, 2.0 Hz, 1H), 7.55 (t, J=7.5 Hz,1H), 7.28 (d, J=8.0 Hz, 2H), 7.24 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.09(s, 2H), 3.34 (s, 2H), 2.97 (q, J=6.0 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H),1.43-1.34 (m, 2H), 1.26 (t, J=7.5 Hz, 3H), 0.81 (t, J=7.5 Hz, 3H); APCIMS m/z 408 [M+H]⁺.

EXAMPLE 1942-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-N-methyl-N-propylacetamide

To a stirred solution of crude2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetylchloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was addedN-methyl-n-propylamine (0.10 mL, 1.00 mmol) followed bydiisopropylethylamine (0.17 mL, 1.00 mmol). After stirring for 3 h thereaction mixture was diluted with dichloromethane (50 mL) and water (5mL). The mixture was acidified with 2N aqueous HCl until pH ˜5. Theorganic layer was washed with saturated sodium chloride (5 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by chromatography on silica using hexanes/ethylacetate (10:0 to 1:1) as eluent followed by preparative HPLC(water/acetonitrile with 0.05% TFA) to afford the title compound (0.040g, 48%) as a colorless oil. MW=421.96. ¹H NMR (DMSO-d₆, 500 MHz) δ8.37-8.33 (m, 2H), 7.59 (dt, J=7.5, 2.0 Hz, 1H), 7.55 (t, J=7.5 Hz, 1H),7.29 (d, J=8.0 Hz, 2H), 7.25 (d, J=5.5 Hz, 1H), 7.18 (t, J=8.0 Hz, 2H),4.10 (s, 2H), 3.63 (d, J=4.0 Hz, 2H), 3.27-3.19 (m, 2H), 2.94 (s, 1.6H),2.81-2.79 (m, 3.4H), 1.47-1.37 (m, 2H), 1.26 (t, J=7.5 Hz, 3H),0.80-0.73 (m, 3H); APCI MS m/z 422 [M+H]⁺.

EXAMPLE 1952-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-N-(2-hydroxyethyl)acetamide

To a stirred solution of crude2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)acetylchloride (˜0.20 mmol) in dichloromethane (8 mL) at 0° C. was addedethanolamine (0.060 mL, 1.00 mmol) followed by diisopropylethylamine(0.17 mL, 1.00 mmol). After stirring for 3 h, the reaction mixture wasdiluted with dichloromethane (50 mL) and water (5 mL). The mixture wasacidified with 2N aqueous HCl until pH ˜5. The organic layer was washedwith saturated sodium chloride (5 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as eluent followed by preparative HPLC (water/acetonitrile with0.05% TFA) to afford the title compound (0.036 g, 45%) as a white solid.MW=409.91. M.p. 136-138° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.37-8.31 (m,2H), 8.02-7.96 (m, 1H), 7.59 (dt, J=6.5, 2.0 Hz, 1H), 7.55 (t, J=8.0 Hz,1H), 7.28 (d, J=8.0 Hz, 2H), 7.25 (s, 1H), 7.20 (d, J=8.0 Hz, 2H), 4.63(t, J=5.0 Hz, 1H), 4.09 (s, 2H), 3.40-3.35 (m, 4H), 3.90 (q, J=6.0 Hz,2H), 2.77 (q, J=7.5 Hz, 2H), 1.26 (t, J=7.5 Hz, 3H); APCI MS m/z 410[M+H]⁺.

EXAMPLE 1962-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanamide

Step 1. Preparation of methyl 2-(p-tolyl)acetate

A 500-mL round bottom flask, with stirrer bar, was charged withp-tolylacetic acid (10.0 g, 66.5 mmol) and methanol (240 mL).Concentrated sulfuric acid (0.1 mL) was added at room temperature. Theresulting solution was stirred at 65° C. for 18 h. After this time, themixture was concentrated in vacuo, and the residue was diluted withethyl acetate (100 mL) and saturated sodium bicarbonate (50 mL). Theorganic layer was washed with saturated sodium chloride (2×20 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressureto afford the title compound (11.8 g, 100%) as a colorless oil.MW=164.20. ¹H NMR (CDCl₃, 300 MHz) δ 7.20-7.10 (m, 4H), 3.68 (s, 3H),3.59 (s, 2H), 2.33 (s, 3H).

Step 2: Preparation of methyl 2-methyl-2-(p-tolyl)propanoate

A 500-mL round bottom flask, with stirrer bar, was charged with2-(p-tolyl)acetate (11.8 g, 66.5 mmol), dimethylformamide (24 mL) andtetrahydrofuran (240 mL) then cooled to 0° C. Sodium hydride (2.92 g,60% suspension, 73.0 mmol) was added portionwise over 3 minutes. Afterstirring for 30 minutes, iodomethane (4.55 mL, 73.0 mmol) was addeddropwise over 5 minutes and the mixture stirred for 1 hour. After thistime, additional sodium hydride (2.92 g, 60% suspension, 73.0 mmol, 1.1eq.) was added portionwise over 8 minutes to the suspension and themixture stirred an additional 30 minutes. After this time, iodomethane(4.55 mL, 73.0 mmol) was added dropwise over 5 minutes. The resultingmixture was allowed to slowly warm to room temperature and stirred for48 h. The reaction was then quenched with water (250 mL) and dilutedwith MTBE (300 mL). The aqueous layer was separated and extracted withMTBE (3×100 mL). The combined extract was washed with saturated sodiumchloride (3×50 mL), then dried over sodium sulfate, filtered, andconcentrated under reduced pressure to afford the title compound (13.5g, 100%) as a colorless oil. MW=192.25. ¹H NMR (CDCl₃, 300 MHz) δ7.25-7.10 (m, 4H), 3.64 (s, 3H), 2.32 (s, 3H), 1.57 (s, 6H).

Step 3. Preparation of methyl2-(4-(bromomethyl)phenyl)-2-methylpropanoate

A 500-mL round bottom flask, with stirrer bar, was charged with methyl2-methyl-2-(p-tolyl)propanoate (2.50 g, 13.0 mmol), NBS (2.31 g, 13.0mmol), and carbon tetrachloride (240 mL). The resulting solution washeated at reflux and AIBN (0.043 g, 0.26 mmol) was added. After stirringfor 3.5 h, the reaction was cooled to room temperature and the solidsremoved by filtration. The filtrate was concentrated under reducedpressure. The residue was purified by chromatography on silica usinghexane/ethyl acetate (100:0 to 80:20) as eluent as eluent to afford thetitle compound (2.20 g, 62%.) as a colorless oil. MW=271.15. ¹H NMR(CDCl₃, 300 MHz) δ 7.39-7.28 (m, 4H), 4.48 (s, 2H), 3.65 (s, 3H), 1.57(s, 6H).

Step 4: Preparation of ethyl2-methyl-2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)propanoate

A 500-mL round bottom flask, with stirrer bar, was charged with methyl2-(4-(bromomethyl)phenyl)-2-methylpropanoate (2.06 g, 7.59 mmol),pinacol diborane (2.31 g, 9.11 mmol),tetrakis(triphenylphosphine)palladium(0) (0.88 g, 0.76 mmol), and K₂CO₃(3.15 g, 22.8 mmol). Dioxane (60 mL) was added and the resulting mixturewas stirred under Ar at 80° C. for 20 h. After this time, the mixturewas cooled to room temperature, diluted with ethyl acetate (200 mL), andfiltered through celite. The filtrate was washed with brine (4×50 mL),dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue (4.4 g) was purified by chromatography on silicausing hexane/ethyl acetate (100:0 to 50:50) as eluent to afford thetitle compound (1.07 g, 44%) as a colorless oil. MW=318.22. ¹H NMR(CDCl₃, 500 MHz) δ 7.22-7.11 (m, 4H), 3.64 (s, 3H), 2.26 (s, 2H), 1.55(s, 6H), 1.24 (s, 12H).

Step 5: Preparation of methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoate

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6-ethylpyrimidine (0.303 g, 1.20 mol),methyl2-methyl-2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)propanoate(0.420 g, 1.32 mmol), Pd(dppf)Cl₂ (0.098 g, 0.12 mmol), and powderedNa₂CO₃ (0.380 g, 3.60 mmol). Dioxane (6 mL) and water (3 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 2 h. After thistime, the mixture was cooled to room temperature and filtered throughcelite washing with ethyl acetate until the filtrate was colorless. Thefiltrate was washed with saturated sodium chloride (3×25 mL) then driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue (0.87 g) was purified by chromatography on silica usinghexane/dichloromethane (10:0 to 8:2) as eluent to afford the titlecompound (0.47 g, 96%) as a colorless oil. MW=408.92. ¹H NMR (CDCl₃, 300MHz) δ 8.50-8.47 (m, 1H), 8.40-8.35 (m, 1H), 7.46-7.37 (m, 2H),7.31-7.24 (m, 4H), 6.87 (s, 1H), 4.10 (s, 2H), 3.65 (s, 3H), 2.77 (q,J=7.8 Hz, 2H), 1.57 (s, 6H), 1.32 (t, J=7.5 Hz, 3H).; ESI MS m/z 409[M+H]⁺.

Step 6. Preparation of2-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoicacid

An 250-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoate(0.472 g, 1.15 mmol), dioxane (24 ml) and water (12 ml). To thissolution was then added lithium hydroxide monohydrate (0.242 g, 5.77mmol). The resulting mixture was stirred at 50° C. for 7 h. After thistime the reaction mixture was cooled and treated with 2M aqueous HCluntil pH ˜5. The volatile materials were removed under reduced pressureto afford the title compound (0.70 g, >100%) as a white solid.MW=394.89. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.26 (br s, 1H), 8.38-8.34 (m,2H), 7.61-7.53 (m, 2H), 7.35-7.27 (m, 5H), 4.09 (s, 2H), 2.78 (q, J=8.0Hz, 2H), 1.44 (s, 6H), 1.27 (t, J=7.5 Hz, 3H). ESI MS m/z 395 [M+H]⁺.

EXAMPLE 1962-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanamide

An 250-mL round bottom flask was charged with2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoicacid (0.35 g, ˜0.57 mmol) in dichloromethane (10 ml) and dioxane (10mL). To this mixture at 0° C. was added oxalyl chloride (0.24 mL, 2.87mmol) followed by DMF (1 drop). After stirring for 6 h, the volatilematerial was removed under reduced pressure to afford crude acidchloride. The residue was dissolved in dichloromethane (24 mL), cooledto 0° C. and 7N ammonia in methanol (10.0 mL, 70 mmol) was added. Afterstirring for 15 h the volatile material was removed under reducedpressure. The residue was diluted with dichloromethane (125 mL) andwashed with saturated sodium chloride (3×15 mL), dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica using hexanes/ethyl acetate aseluent followed by preparative HPLC (water/acetonitrile with 0.05% TFA)to afford the title compound (0.057 g, 24%) as a yellow-orange solid.MW=393.91. M.p. 35-37° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.38-8.34 (m, 2H),7.61-7.54 (m, 2H), 7.34-7.27 (m, 5H), 6.82 (br s, 2H), 4.09 (s, 2H),2.78 (q, J=7.5 Hz, 2H), 1.40 (s, 6H), 1.27 (t, J=7.5 Hz, 3H). APCI MSm/z 394 [M+H]⁺.

EXAMPLE 1972-(4-((2-(3-Chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropan-1-ol

A 25-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6-ethylpyrimidin-4-yl)methyl)phenyl)-2-methylpropanoate(0.259 g, 0.57 mmol) and THF (6 mL) at rt. Borane-dimethylsulfidecomplex (0.158 mL, 1.67 mmol) was added and the resulting solution wasstirred at 55° C. for 2.5 h. LCMS analysis indicated only partialreduction. Borane-dimethylsulfide complex (0.100 mL, 1.05 mmol) wasadded and the resulting solution was stirred at 55° C. for a further 19h until the starting material was consumed (monitored by LCMS analysis).The reaction was quenched with methanol then treated with 2N aqueous HCl(0.1 mL) and concentrated under reduced pressure. The residue wasdiluted with methanol and then concentrated under reduced pressure. Theresidue absorbed onto silica (2 g) then purified by columnchromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) asthe eluent to afford the title compound (0.078 g, 36%) as a colorlessoil. MW=380.91. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.38-8.34 (m, 2H), 7.61-7.54(m, 2H), 7.33-7.26 (m, 5H), 4.60 (t, J=5.5 Hz, 1H), 4.07 (s, 2H), 3.38(d, J=5.5 Hz, 2H), 2.78 (q, J=7.5 Hz, 2H), 1.27 (t, J=7.5 Hz, 3H), 1.18(s, 6H); APCI MS m/z 381 [M+H]⁺.

EXAMPLE 1982-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of4-chloro-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine

A 250-mL round bottom flask was charged with4-chloro-2-(methylthio)-6-(trifluoromethyl)pyrimidine (2.50 g, 10.9mmol) in dichloromethane (20 mL). To this solution at 0° C. was added asolution of m-CPBA in dichloromethane (40 mL) over 7 minutes. Afterstirring for 7 h, the reaction mixture diluted with dichloromethane andwashed with saturated sodium thiosulfate (25 mL), saturated sodiumcarbonate (2×10 mL), and saturated sodium chloride (2×10 mL). Theorganic layer was dried over sodium sulfate, filtered, and concentratedunder reduced pressure to afford the title compound (2.89 g, 100%) as awhite solid. MW=260.62. ¹H NMR (CDCl₃, 300 MHz) δ 7.90 (s, 1H), 3.44 (s,3H).

Step 2. Preparation of4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine

To a stirred solution of cyclopentanol (0.61 mL, 6.75 mmol) intetrahydrofuran (24 mL) at 0° C. was added potassium tert-butoxide (0.76g, 6.75 mmol). The resulting yellow solution was added dropwise to astirred solution of4-chloro-2-(methylsulfonyl)-6-(trifluoromethyl)pyrimidine (1.76 g, 6.75mmol) in tetrahydrofuran (24 mL) at −78° C. over 15 minutes. Thereaction was then stirred at −78° C. for 2 h then allowed to warm to rt.After stirring for 15 h at room temperature, the reaction was quenchedwith water (20 mL) and diluted with ethyl acetate (200 mL). The aqueouslayer was extracted with ethyl acetate (2×74 mL). The combined organicextract was washed with saturated sodium chloride (2×20 mL), dried oversodium sulfate, filtered, and concentrated under reduced pressure. Theresidue was purified by chromatography on silica using hexanes/ethylacetate (10:0 to 0:10) as eluent to afford the title compound (0.60 g,33%) as a colorless oil. MW=266.65. ¹H NMR (CDCl₃, 500 MHz) δ 7.26 (s,1H), 5.48 (sept, J=3.0 Hz, 1H), 2.08-1.76 (m, 6H), 1.75-1.58 (m, 2H).

EXAMPLE 1982-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide

A 10-mL microwave vial was charged with4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34mmol) and (4-aminophenyl)acetamide (0.076 g, 0.51 mmol) in NMP (3 mL).The resulting mixture was heated at 120° C. under microwave irradiationfor 1 h. The reaction mixture was cooled, diluted with water (50 mL)affording a solid. The solid was isolated by filtration andchromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) aseluent to afford the title compound (0.067 g, 52%) as a white solid.MW=380.36. M.p. 208-210° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.05 (s, 1H),7.58 (br d, J=7.5 Hz, 2H), 7.42 (s, 1H), 7.25 (d, J=7.5 Hz, 2H), 6.85(s, 1H), 6.74 (s, 1H), 5.31 (septet, J=3.0 Hz, 1H), 2.01-1.90 (m, 2H),1.80-1.66 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]⁺.

EXAMPLE 1992-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)ethanol

A 10-mL microwave vial was charged with4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.090 g, 0.34mmol) and (4-aminophenyl)ethyl alcohol (0.069 g, 0.51 mmol) in NMP (3mL). The resulting mixture was heated at 120° C. under microwaveirradiation for 1 h. After this time, the reaction mixture was cooledand diluted with water (50 mL) affording a solid. The solid was isolatedby filtration and chromatography on silica using hexanes/ethyl acetate(10:0 to 0:10) as eluent to afford the title compound (0.087 g, 70%) asa white solid. MW=367.37. M.p. 173-175° C. ¹H NMR (DMSO-d₆, 500 MHz) δ10.01 (s, 1H), 7.56 (br d, J=7.0 Hz, 2H), 7.22 (d, J=8.5 Hz, 2H), 6.73(s, 1H), 5.30 (septet, J=3.0 Hz, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.62-3.57(m, 2H), 2.70 (t, J=7.0 Hz, 2H), 2.00-1.90 (m, 2H), 1.80-1.66 (m, 4H),1.65-1.55 (m, 2H); APCI MS m/z 368 [M+H]⁺.

EXAMPLE 2002-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)aceticacid

Step 1. Preparation of methyl2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidine (0.400 g, 1.50mol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.478 g, 1.65 mmol), Pd(dppf)Cl₂ (0.122 g, 0.15 mmol), and powderedNa₂CO₃ (0.477 g, 4.50 mmol). Dioxane (8 mL) and water (4 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 2.5 h. Afterthis time, the mixture was cooled to room temperature and filteredthrough celite washing with ethyl acetate until the filtrate wascolorless. The aqueous layer was separated and the organic layer waswashed with saturated sodium chloride (2×10 mL) then dried over sodiumsulfate, filtered and concentrated under reduced pressure. The residuewas purified by chromatography on silica using hexane/ethyl acetate(10:0 to 3:1) as eluent to afford the title compound (0.40 g, 67%) as ayellow oil. MW=394.39. ¹H NMR (CDCl₃, 300 MHz) δ 7.25 (s, 4H), 7.14 (s,1H), 5.46 (septet, J=3.0 Hz, 1H), 4.08 (s, 2H), 3.69 (s, 3H), 3.62 (s,2H), 2.04-1.73 (m, 6H), 1.72-1.56 (m, 2H); ESI MS m/z 327 [M-C₅H₉+2H]⁺.

EXAMPLE 2002-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)aceticacid

An 100-mL round bottom flask was charged with methyl2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.100 g, 0.25 mmol), dioxane (6 ml) and water (3 ml). To thissolution was then added lithium hydroxide monohydrate (0.053 g, 1.26mmol). The resulting mixture was stirred at 50° C. for 1.5 h. The cooledreaction mixture was treated with 2N aqueous HCl until pH ˜5, thendiluted with ethyl acetate (75 mL). The organic layer was washed withsaturated sodium chloride (5 mL), dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bychromatography on silica using hexane/ethyl acetate (10:0 to 0:10) asthe eluent, followed by preparative HPLC (water/acetonitrile with 0.05%TFA) to afford the title compound (0.051 g, 53%) as an off-white solid.MW=380.36. M.p. 97-99° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.28 (br s, 1H),7.52 (s, 1H), 7.28 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 5.35(septet, J=3.0 Hz, 1H), 4.11 (s, 2H), 3.52 (s, 2H), 2.00-1.89 (m, 2H),1.77-1.65 (m, 4H), 1.65-1.55 (m, 2H); APCI MS m/z 381 [M+H]⁺.

EXAMPLE 2012-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetamide

A 20-mL vial was charged with methyl2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.150 g, 0.38 mmol) in methanol (2 mL). To this mixture wasadded NH₃ (10.8 mL, 7N in methanol, 76.0 mmol). The vial was sealed andthe resulting mixture was stirred at 100° C. for 23 h. The crudereaction solution concentrated under reduced pressure. The residue waspurified by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as eluent followed by chromatography on silica usingdichloromethane/methanol (10:0 to 96:4) as eluent to afford the titlecompound (0.066 g, 46%) as a white solid. MW=379.38. M.p. 130-132° C. ¹HNMR (DMSO-d₆, 500 MHz) δ 7.51 (s, 1H), 7.41 (br s, 1H), 7.26 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 6.83 (br s, 1H), 5.35 (septet, J=3.0Hz, 1H), 4.10 (s, 2H), 3.33 (s, 2H), 2.00-1.90 (m, 2H), 1.77-1.66 (m,4H), 1.65-1.55 (m, 2H); ESI MS m/z 380 [M+H]⁺.

EXAMPLE 2022-(4-((2-(Cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)ethanol

A 25-mL round bottom flask was charged with methyl2-(4-((2-(cyclopentyloxy)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate (0.069 g, 0.17 mmol) and dichloromethane (6 mL) at 0° C. A 1Msolution of DIBAL-H in THF (0.70 mL, 0.70 mmol) was added and theresulting solution was stirred at 0° C. for 1 h until the startingmaterial was consumed (monitored by LCMS analysis). The reaction wasquenched with methanol then absorbed onto silica (2 g) and concentratedunder reduced pressure. Purification by column chromatography on silicausing hexanes/ethyl acetate (10:0 to 1:1) as the eluent afforded thetitle compound (0.055 g, 87%) as a white solid. MW=366.38. M.p. 48-50°C. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.51 (s, 1H), 7.23 (d, J=7.5 Hz, 2H),7.16 (d, J=8.0 Hz, 2H), 5.38-5.32 (m, 1H), 4.58 (t, J=5.5 Hz, 1H), 4.09(s, 2H), 3.56 (q, J=6.0 Hz, 2H), 2.68 (t, J=7.0 Hz, 2H), 2.00-1.89 (m,2H), 1.77-1.66 (m, 4H), 1.66-1.55 (m, 2H); APCI MS m/z 367 [M+H]⁺.

EXAMPLE 203 Methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate

Step 1. Preparation of2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one

A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide(4.81 g, 25.3 mmol), ethyl 4,4,4-trifluoro-3-oxobutanoate (5.00 g, 27.1mmol), and ethanol (90 mL) and cooled to 0° C. A 25% sodium methoxidesolution in methanol (13.0 mL, 55.3 mmol) was added to the mixture. Theresulting mixture was stirred at reflux for 20 h. After this time, themixture was cooled to room temperature and concentrated under reducedpressure to 25 mL. The residual slurry was cautiously treated with 2NHCl (50 mL) forming a solid. The solid was collected by filtration andwashed with water followed by ether to afford the title compound (3.60g, 48%) as a white solid, which was carried forward into the next stepwithout further purification. MW=274.63. ¹H NMR (DMSO-d₆, 500 MHz) δ13.39 (s, 1H), 8.18 (s, 1H), 8.10 (d, J=7.5 Hz, 1H), 7.73-7.69 (m, 1H),7.60 (t, J=8.0 Hz, 1H), 6.94 (s, 1H).

Step 2. Preparation of4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine

A 250-mL round bottom flask was charged with2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4(3H)-one (3.60 g, 13.1mmol). POCl₃ (14.4 mL, 157 mmol) was cautiously added at 0° C. Theresulting mixture was stirred at 100° C. for 3.5 h. After cooling toroom temperature, the mixture was concentrated under reduced pressure.The residue was dissolved in dichloromethane (50 mL) and treated withaqueous sodium bicarbonate until the pH ˜8. The aqueous layer wasextracted with dichloromethane (4×25 mL). The combined organic extractwas washed the saturated sodium chloride (20 mL), dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica chromatography using hexanes/dichloromethane(3:1) as eluent to afford the title compound (3.36 g, 87%) as a whitesolid. MW=293.07. ¹H NMR (CDCl₃, 500 MHz) δ 8.49 (t, J=1.5 Hz, 1H), 8.39(dt, J=8.0, 1.5 Hz, 1H), 7.57 (s, 1H), 7.53 (ddd, J=8.0, 2.0, 1.0 Hz,1H), 7.45 (t, J=8.0 Hz, 1H).

EXAMPLE 203 Methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.404 g, 1.38mol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.400 g, 1.38 mmol), Pd(dppf)Cl₂ (0.113 g, 0.14 mmol), and powderedNa₂CO₃ (0.438 g, 4.14 mmol). Dioxane (6 mL) and water (3 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 1.25 h. Afterthis time, the mixture was cooled to room temperature and filteredthrough celite washing with ethyl acetate until the filtrate wascolorless. The aqueous layer was separated and the organic layer waswashed with saturated sodium chloride (2×5 mL) then dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by chromatography on silica using hexane/ethyl acetate(95:5 to 2:1) as eluent to afford the title compound (0.284 g, 49%) as alight orange solid. MW=420.81. M.p. 70-72° C. ¹H NMR (DMSO-d₆, 500 MHz)δ 8.36-8.33 (m, 2H), 7.68 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.62 (t, J=8.0Hz, 1H), 7.37 (d, J=7.0 Hz, 2H), 7.24 (d, J=8.0 Hz, 2H), 4.31 (s, 2H),3.64 (s, 2H), 3.59 (s, 3H); ESI MS m/z 421 [M+H]⁺.

EXAMPLE 2042-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetamide

A 20-mL vial was charged with methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate(0.136 g, 0.32 mmol) and ammonium chloride (0.052 g, 0.97 mmol, 3.0 eq.)in methanol (4 mL). To this mixture was added NH₃ (8.0 mL, 7N inmethanol, 56.0 mmol). The vial was sealed and the resulting mixture wasstirred at 100° C. for 70 h. After this time, the crude reaction wasconcentrated under reduced pressure and the residue absorbed on silica(2 g) then purified by chromatography on silica using hexanes/ethylacetate (10:0 to 0:10) as eluent followed by preparative HPLC(water/acetonitrile with 0.05% TFA) to afford the title compound (0.088g, 67%) as a white solid. MW=405.80. M.p. 170-172° C. ¹H NMR (DMSO-d₆,500 MHz) δ 8.37-8.33 (m, 2H), 7.93 (s, 1H), 7.68 (ddd, J=8.0, 2.0, 1.0Hz, 1H), 7.62 (t, J=8.0 Hz, 1H), 7.43 (br s, 1H), 7.34 (d, J=8.0 Hz,2H), 7.23 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.30 (s, 2H), 3.33 (s,2H); APCI MS m/z 406 [M+H]⁺.

EXAMPLE 2052-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)ethanol

A 25-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate(0.126 g, 0.30 mmol) and THF (4 mL) at rt. Borane-dimethylsulfidecomplex (0.085 mL, 0.90 mmol) was added and the resulting solution wasstirred at 55° C. for 2 h. LCMS analysis indicated only partialreduction. Borane-dimethylsulfide complex (0.045 mL, 0.47 mmol) wasadded and the resulting solution was stirred at 55° C. for a further 2.5h until the starting material was consumed (monitored by LCMS analysis).The reaction was quenched with methanol then treated with 2N aqueous HCl(5 drops) and concentrated under reduced pressure. The residue wasdiluted with methanol and then concentrated under reduced pressure. Theresidue absorbed onto silica (2 g) then purified by columnchromatography on silica using hexanes/ethyl acetate (10:0 to 3:1) asthe eluent to afford the title compound (0.086 g, 73%) as an orangesolid. MW=392.80. M.p. 78-80° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.37-8.33(m, 2H), 7.93 (s, 1H), 7.68 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.62 (t,J=8.0 Hz, 1H), 7.32 (d, J=8.0 Hz, 2H), 7.18 (d, J=8.0 Hz, 2H), 4.59 (brs, 1H), 4.28 (s, 2H), 3.57 (d, J=7.0 Hz, 2H), 2.68 (d, J=7.0 Hz, 2H);APCI MS m/z 393 [M+H]⁺.

EXAMPLE 2062-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4(3H)-one

A 500-mL round bottomed flask was charged with 3-chlorobenzimidamide(5.75 g, 30.1 mmol), ethyl 3-cyclopropyl-3-oxopropanoate (5.00 g, 32.0mmol), and ethanol (100 mL) and the mixture cooled to 0° C. To thestirred mixture was added 25% sodium methoxide in methanol (15.0 mL,64.0 mmol). The resulting mixture was stirred at reflux for 20 h. Aftercooling to room temperature, the mixture was evaporated under reducedpressure to 25 mL. The residual slurry was cautiously treated with 2NHCl (50 mL) forming a solid. The solid was collected by filtration andwashed with water followed by ether to afford the title compound (2.46g, 31%) as a white solid, which was carried forward into the next stepwithout further purification. MW=246.69. ¹H NMR (DMSO-d₆, 500 MHz) δ12.55 (s, 1H), 8.13 (s, 1H), 8.06 (d, J=7.5 Hz, 1H), 7.64-7.60 (m, 1H),7.54 (t, J=8.0 Hz, 1H), 6.34 (s, 1H), 2.00-1.93 (m, 1H), 1.08-1.02 (m,2H), 0.99-0.91 (m, 2H).

Step 2. Preparation of4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine

A 250-mL round bottom flask was charged with2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4(3H)-one (2.46 g, 9.97 mmol).POCl₃ (11.0 mL, 120 mmol) was cautiously added at 0° C. The resultingmixture was stirred at 100° C. for 1.5 h. After cooling to roomtemperature, the mixture was concentrated under reduced pressure. Theresidue was dissolved in dichloromethane (50 mL) treated with aqueoussodium bicarbonate until the pH ˜8. The aqueous layer was extracted withdichloromethane (4×25 mL). The combined organic extract was washed thesaturated sodium chloride (20 mL), dried over sodium sulfate, filtered,and concentrated under reduced pressure. The residue was purified bysilica chromatography using hexanes/dichloromethane (3:1) as eluent toafford the title compound (2.55 g, 96%) as a white solid. MW=265.14. ¹HNMR (CDCl₃, 500 MHz) δ 8.38 (t, J=1.5 Hz, 1H), 8.28 (dt, J=8.0, 1.5 Hz,1H), 7.44 (ddd, J=8.0, 2.0, 1.0 Hz, 1H), 7.38 (t, J=8.0 Hz, 1H), 7.12(s, 1H), 2.04-1.97 (m, 1H), 1.33-1.27 (m, 2H), 1.18-1.13 (m, 2H).

EXAMPLE 2062-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)phenyl)ethanol

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.100 g, 0.38 mmol)and 4-aminophenethyl alcohol (0.103 g, 0.75 mmol) in NMP (3 mL). Theresulting mixture was heated at 120° C. under microwave irradiation for1 h. The reaction mixture was cooled, diluted with water (20 mL)affording a solid. The solid was isolated by filtration and purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 1:1) aseluent to afford the title compound (0.101 g, 73%) as a white solid.MW=365.86. M.p. 124-126° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.46 (s, 1H),8.27-8.21 (m, 2H), 7.62-7.51 (m, 4H), 7.21 (d, J=8.5 Hz, 2H), 6.62 (s,1H), 4.61 (br s, 1H), 3.60 (t, J=7.0 Hz, 2H), 2.70 (t, J=7.0 Hz, 2H),2.06-1.99 (m, 1H), 1.11-1.06 (m, 2H), 1.02-0.95 (m, 2H); ESI MS m/z 366[M+H]⁺.

EXAMPLE 2072-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)phenyl)acetamide

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.100 g, 0.38 mmol)and (4-aminophenyl)acetamide (0.113 g, 0.75 mmol) in NMP (3 mL). Theresulting mixture was heated at 120° C. under microwave irradiation for2 h. The reaction mixture was cooled, diluted with water (50 mL)affording a solid. The solid was isolated by filtration and purified bychromatography on silica using hexanes/ethyl acetate (10:0 to 0:10) aseluent to afford the title compound (0.107 g, 78%) as a white solid.MW=378.85. M.p. 174-176° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 9.51 (s, 1H),8.27-8.22 (m, 2H), 7.61 (d, J=8.0 Hz, 2H), 7.57-7.52 (m, 2H), 7.43 (brs, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.85 (br s, 1H), 6.63 (s, 1H), 3.35 (s,2H), 2.07-2.00 (m, 1H), 1.12-1.06 (m, 2H), 1.03-0.95 (m, 2H); ESI MS m/z379 [M+H]⁺.

EXAMPLE 208 Methyl2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)methyl)phenyl)acetate

A 20-mL sealed tube, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.365 g, 1.38 mol),methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.400 g, 1.38 mmol), Pd(dppf)Cl₂ (0.113 g, 0.14 mmol), and powderedNa₂CO₃ (0.438 g, 4.14 mmol). Dioxane (6 mL) and water (3 mL) were added.The resulting mixture was stirred under Ar at 90° C. for 1.5 h until thestarting chloride was consumed. After cooling to room temperature, thereaction mixture was filtered through celite washing with ethyl acetateuntil the filtrate was colorless. The aqueous layer was separated andthe organic layer was washed with saturated sodium chloride (2×5 mL)then dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by chromatography on silica usinghexane/ethyl acetate (95:5 to 1:2) as eluent to afford the titlecompound (0.285 g, 52%) as a colorless oil. MW=392.88. ¹H NMR (DMSO-d₆,500 MHz) δ 8.30-8.27 (m, 2H), 7.59-7.51 (m, 2H), 7.31 (d, J=8.0 Hz, 2H),7.28 (s, 1H), 7.21 (d, J=8.0 Hz, 2H), 4.07 (s, 2H), 3.64 (s, 2H), 3.59(s, 3H), 2.16-2.09 (m, 1H), 1.16-1.05 (m, 4H); ESI MS m/z 393 [M+H]⁺.

EXAMPLE 2092-(4-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)methyl)phenyl)acetamide

A 20-mL vial was charged with methyl2-(4-((2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate(0.125 g, 0.32 mmol) and ammonium chloride (0.051 g, 0.95 mmol) inmethanol (4 mL). To this mixture was added NH₃ (6.0 mL, 7N in methanol,42.0 mmol). The vial was sealed and the resulting mixture was stirred at100° C. for 69 h. After this time, the reaction mixture was concentratedunder reduced pressure, the residue was absorbed on silica (2 g), andthen purified by chromatography on silica using hexanes/ethyl acetate(10:0 to 0:10) as eluent to afford the title compound (0.095 g, 79%) asa white solid. MW=377.87. M.p. 161-163° C. ¹H NMR (DMSO-d₆, 500 MHz) δ8.31-8.27 (m, 2H), 7.59-7.51 (m, 2H), 7.41 (br s, 1H), 7.30-7.25 (m,3H), 7.21 (d, J=8.0 Hz, 2H), 6.82 (br s, 1H), 4.06 (s, 2H), 3.33 (s,2H), 2.17-2.09 (m, 1H), 1.16-1.05 (m, 4H); ESI MS m/z 378 [M+H]⁺.

EXAMPLE 2102-(4-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)methyl)phenyl)ethanol

A 25-mL round bottom flask was charged with methyl2-(4-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)methyl)phenyl)acetate(0.149 g, 0.38 mmol) and THF (5 mL) at rt. Borane-dimethylsulfidecomplex (0.108 mL, 1.13 mmol) was added and the resulting solution wasstirred at 55° C. for 2.5 h until the starting material was consumed(monitored by LCMS analysis). The reaction was quenched with methanolthen treated with 2N aqueous HCl (5 drops) and concentrated underreduced pressure. The residue was diluted with methanol and thenconcentrated under reduced pressure. The residue was absorbed ontosilica (2 g) and purified by column chromatography on silica usinghexanes/ethyl acetate (10:0 to 3:1) as the eluent to afford the titlecompound (0.113 g, 82%) as a colorless oil. MW=364.87. ¹H NMR (DMSO-d₆,500 MHz) δ 8.31-8.27 (m, 2H), 7.59-7.51 (m, 2H), 7.27 (s, 1H), 7.26 (d,J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 4.58 (t, J=5.0 Hz, 1H), 4.04 (s,2H), 3.59-3.52 (m, 2H), 2.68 (t, J=7.0 Hz, 2H), 2.16-2.09 (m, 1H),1.16-1.05 (m, 4H); APCI MS m/z 365 [M+H]⁺.

EXAMPLE 211 Ethyl2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetate

A 20-mL vial was charged with4-chloro-2-(3-chlorophenyl)-6-cyclopropylpyrimidine (0.380 g, 1.43mmol), ethyl 2-(6-aminopyridin-3-yl)acetate (0.410 g, 2.27 mmol),palladium acetate (0.016 g, 0.071 mmol), rac-BINAP (0.069 g, 0.11 mmol)and cesium carbonate (1.17 g, 3.58 mmol) in dioxane (10 mL) under argon.The reaction mixture was heated to 110° C. under microwave irradiationfor 1.25 h. The reaction mixture was cooled, and diluted with ethylacetate and filtered through celite. The filtrate was washed withsaturated sodium chloride (2×10 mL), dried over sodium sulfate,filtered, and the filtrate concentrated under reduced pressure. Theresidue was purified by chromatography on silica using hexanes/ethylacetate (10:0 to 0:10) as eluent to afford the title compound (0.504 g,86%) as an off-white solid. MW=408.88. M.p. 133-135° C. ¹H NMR (DMSO-d₆,500 MHz) δ 10.13 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0, 1.5 Hz,1H), 8.22 (d, J=2.0 Hz, 1H), 7.75-7.68 (m, 2H), 7.62 (br s, 1H),7.59-7.52 (m, 2H), 4.10 (q, J=7.5 Hz, 2H), 3.68 (s, 2H), 2.07 (septet,J=4.5 Hz, 1H), 1.21 (t, J=7.0 Hz, 3H), 1.14-1.10 (m, 2H), 1.06-1.00 (m,2H); APCI MS m/z 409 [M+H]⁺.

EXAMPLE 2122-(6-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetamide

A 10-mL vial was charged with ethyl2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetate(0.070 g, 0.17 mmol) and NH₃ (4.9 mL, 7N in methanol, 34.2 mmol). Thevial was sealed and the resulting mixture was stirred at 100° C. for 23h. The crude reaction solution concentrated under reduced pressure. Theresidue was absorbed on silica (2 g) then purified by chromatography onsilica using dichloromethane/methanol (10:0 to 9:1) as eluent to affordthe title compound (0.029 g, 45%) as a white solid. M.p. 232-235° C. ¹HNMR (DMSO-d₆, 500 MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt,J=7.5, 2.0 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.75-7.69 (m, 1H), 7.67 (dd,J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 7.50 (br s, 1H),6.93 (br s, 1H), 3.37 (s, 2H), 2.07 (septet, J=4.5 Hz, 1H), 1.14-1.09(m, 2H), 1.06-1.00 (m, 2H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 2132-(6-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)aceticacid

An 250-mL round bottom flask was charged with ethyl2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)acetate(0.417 g, 1.02 mmol), dioxane (20 ml) and water (10 ml). To thissolution was then added lithium hydroxide monohydrate (0.214 g, 5.10mmol). The resulting mixture was stirred at 50° C. for 1.5 h. The cooledreaction mixture was treated with 2N aqueous HCl until pH ˜4 affording asolid. The solid was isolated by filtration and dried under reducedpressure at 55° C. to afford the title compound (0.408 g, 100%) as awhite solid. MW=380.83. M.p.>260° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.33(br s, 1H), 10.41 (s, 1H), 8.32-8.24 (m, 3H), 7.80-7.70 (m, 2H),7.60-7.52 (m, 3H), 3.62 (s, 2H), 2.10 (septet, J=4.5 Hz, 1H), 1.16-1.10(m, 2H), 1.10-1.02 (m, 2H); ESI MS m/z 381 [M+H]⁺.

EXAMPLE 2142-(6-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)aceticacid

A 25-mL round bottom flask was charged with2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)aceticacid (0.100 g, 0.26 mmol) and THF (8 mL) at rt. Borane-dimethylsulfidecomplex (124 mL, 1.31 mmol) was added and the resulting solution wasstirred at 55° C. for 1 h until the starting material was consumed(monitored by LCMS analysis). The reaction was quenched with methanolthen treated with 2N aqueous HCl (5 drops) and concentrated underreduced pressure. The residue was diluted with methanol and thenconcentrated under reduced pressure. The residue was absorbed ontosilica (2 g) and purified by column chromatography on silica usingdichloromethane/methanol (10:0 to 9:1) as the eluent, followed bypreparative HPLC (water/acetonitrile with 0.05% TFA) to afford the titlecompound (0.031 g, 32%) as a white solid. M.p. 146-148° C. ¹H NMR(DMSO-d₆, 500 MHz) δ 10.05 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0,1.5 Hz, 1H), 8.20-8.18 (m, 1H), 7.70-7.64 (m, 2H), 7.62 (br s, 1H),7.58-7.52 (m, 2H), 4.67 (br s, 1H), 3.61 (t, J=7.0 Hz, 2H), 3.13 (s,3H), 2.70 (t, J=7.0 Hz, 2H), 2.06 (septet, J=4.5 Hz, 1H), 1.13-1.09 (m,2H), 1.05-1.00 (m, 2H); APCI MS m/z 367 [M+H]⁺.

EXAMPLE 2152-(6-((2-(3-Chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)acetamide

To a stirred suspension of2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)aceticacid (0.185 g, 0.48 mmol) in dimethylformamide (7 mL) at 0° C. was addedethanolamine (0.044 mL, 0.72 mmol, 1.5 eq.) followed bydiisopropylethylamine (0.34 mL, 1.94 mmol, 4.0 eq.) and HATU (0.221 g,0.58 mmol). After stirring for 2 h, the reaction mixture was dilutedwith water (100 mL) and the resulting white solid isolated byfiltration. The solid was purified by chromatography on silica usingdichloromethane/methanol (10:0 to 9:1) as eluent followed by preparativeHPLC (water/acetonitrile with 0.05% TFA) to afford2-(6-((2-(3-chlorophenyl)-6-cyclopropylpyrimidin-4-yl)amino)pyridin-3-yl)-N-(2-hydroxyethyl)acetamide(67 mg, 33%) as a white solid. M.p. 131-133° C. ¹H NMR (DMSO-d₆, 500MHz) δ 10.10 (s, 1H), 8.31-8.29 (m, 1H), 8.27 (dt, J=7.0, 1.5 Hz, 1H),8.19 (d, J=1.5 Hz, 1H), 8.08 (t, J=5.5 Hz, 1H), 7.74-7.69 (m, 1H), 7.67(dd, J=8.5, 2.0 Hz, 1H), 7.60 (br s, 1H), 7.58-7.52 (m, 2H), 4.68 (t,J=5.5 Hz, 1H), 3.44-3.39 (m, 4H), 3.13 (q, J=6.0 Hz, 2H), 2.07 (septet,J=4.5 Hz, 1H), 1.14-1.09 (m, 2H), 1.06-1.00 (m, 2H); APCI MS m/z 424[M+H]⁺.

EXAMPLE 2162-(4-((2-Cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of2-cyclopentyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one

A 250-mL round bottomed flask was charged withcyclopentanecarboximidamide hydrochloride (5.38 g, 36.2 mmol), ethyl2-oxocyclopentanecarboxylate (5.14 g, 38.7 mmol), and ethanol (100 mL).To the stirred mixture at rt was added sodium methoxide (3.91 g, 72.4mmol). The resulting mixture was stirred under reflux for 22 h. Aftercooling to room temperature, the mixture was evaporated under reducedpressure to 25 mL. The residual slurry was cautiously treated with 2NHCl (50 mL). The solution was extracted with ethyl acetate (4×50 mL).The combined extract was washed with saturated sodium chloride (2×25mL), dried over sodium sulfate, filtered, and concentrated under reducedpressure to afford the title compound which was carried forward into thenext step without further purification.

Step 2. Preparation of4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A 250-mL round bottom flask was charged with crude2-cyclopentyl-6,7-dihydro-3H-cyclopenta[d]pyrimidin-4(5H)-one (4.05 g)and POCl₃ (22 mL, 23.8 mmol). The resulting mixture was stirred at 100°C. for 5 h. After cooling to room temperature, the mixture wasconcentrated under reduced pressure. The residue was poured into water(250 mL) and dichloromethane (50 mL) then treated with aqueous sodiumhydroxide until the pH ˜8. The aqueous layer was extracted withdichloromethane (2×50 mL). The combined organic extract was washed thesaturated sodium chloride (2×20 mL), dried over sodium sulfate,filtered, and concentrated under reduced pressure. The residue waspurified by silica on chromatography using dichloromethane/methanol(10:0 to 9:1) as eluent to afford the title compound (0.095 g, 3% over 2steps) as a brown oil. MW=222.71. ¹H NMR (CDCl₃, 300 MHz) δ 3.31 (quin,J=2.4 Hz, 1H), 3.07 (t, J=7.8 Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.22-2.00(m, 4H), 1.98-1.76 (m, 4H), 1.75-1.60 (m, 2H).

EXAMPLE 2162-(4-((2-Cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetamide

A 10-mL microwave vial was charged with4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.132 g,0.59 mmol) and (4-aminophenyl)acetamide (0.178 g, 1.18 mmol) in NMP (4mL). The resulting mixture was heated at 120° C. under microwaveirradiation for 2 h. The reaction mixture was cooled, diluted with water(40 mL), then extracted with 3:1 chloroform/isopropanol (3×25 mL). Thecombined extract was washed with saturated sodium chloride (5 mL), driedover sodium sulfate, filtered, and concentrated under reduced pressure.The residue was purified by chromatography on silica usingdichloromethane/methanol (9:1) as eluent followed by chromatography onsilica using dichloromethane/methanol (10:0 to 9:1) as eluent to affordthe title compound (0.112 g, 56%) as a light brown solid. MW=336.43.M.p. 228-230° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.51 (s, 1H), 7.72 (d,J=8.5 Hz, 2H), 7.39 (s, 1H), 7.16 (d, J=8.5 Hz, 2H), 6.82 (s, 1H), 3.10(quin, J=8.0 Hz, 1H), 2.77 (q, J=9.0 Hz, 4H), 2.01 (quin, J=7.5 Hz, 2H),1.98-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.68 (m, 2H), 1.65-1.55 (m,2H); APCI MS m/z 337 [M+H]⁺.

EXAMPLE 2172-(4-((2-Cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)ethanol

A 10-mL microwave vial was charged with4-chloro-2-cyclopentyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.132 g,0.59 mmol) and 4-aminophenethyl alcohol (0.162 g, 1.18 mmol) in NMP (4mL). The resulting mixture was heated at 120° C. under microwaveirradiation for 2 h. The reaction mixture was cooled, diluted with water(40 mL) to afford a solid. The solid was isolated by filtration thenpurified by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as eluent to afford the title compound (0.098 g, 51%) as alight brown solid. MW=323.43. M.p. 178-180° C. ¹H NMR (DMSO-d₆, 500 MHz)δ 8.47 (s, 1H), 7.70 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H), 4.59 (t,J=5.0 Hz, 1H), 3.61-3.55 (m, 2H), 3.09 (quin, J=8.0 Hz, 1H), 2.77 (q,J=7.5 Hz, 4H), 2.67 (t, J=7.0 Hz, 2H), 2.01 (quin, J=7.5 Hz, 2H),1.97-1.90 (m, 2H), 1.87-1.78 (m, 2H), 1.78-1.68 (m, 2H), 1.65-1.55 (m,2H); APCI MS m/z 324 [M+H]⁺.

EXAMPLE 2184-(4-((4-Chloro-1H-pyrazol-1-yl)methyl)benzyl)-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine

A mixture of 4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine(0.076 g, 0.26 mmol),4-chloro-1-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)benzyl)-1H-pyrazole(0.129 g, 0.39 mmol), Pd(dppf)Cl₂ (0.021 g, 0.03 mmol), and powderedNa₂CO₃ (0.082 g, 0.77 mmol) in dioxane (2 mL) and water (1 mL) wasstirred under an argon atmosphere at 90° C. for 3 h. After this time,the mixture was cooled and filtered through celite with ethyl acetatewashes. The filtrate was washed with brine (3×15 mL), dried over sodiumsulfate, filtered, and concentrated. The residue was purified by columnchromatography (silica, hexane/ethyl acetate) to afford the titlecompound (0.073 g, 98%) as an off-white solid. MW=463.28. ¹H NMR(DMSO-d₆, 300 MHz) δ 8.37-8.30 (m, 2H), 8.07 (s, 1H), 7.96 (s, 1H),7.72-7.66 (m, 1H), 7.65-7.58 (m, 1H), 7.54 (s, 1H), 7.40 (d, J=8.1 Hz,2H), 7.22 (d, J=8.1 Hz, 2H), 5.26 (s, 2H), 4.31 (s, 2H); APCI MS m/z 463[M+H]⁺.

EXAMPLE 2192-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)ethanol

Following General Procedure A2,4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.100 g, 0.34mmol) in NMP (3 mL) was reacted with 4-aminophenethyl alcohol (0.094 g,0.68 mmol) to afford the title compound (0.044 g, 44%) as an off-whitesolid. MW=393.79. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.20 (s, 1H), 8.30-8.25(m, 2H), 7.78-7.56 (m, 4H), 7.29 (d, J=8.5 Hz, 2H), 7.07 (s, 1H), 4.64(t, J=5.2 Hz, 1H), 3.66-3.60 (m, 2H), 2.74 (t, J=7.0 Hz, 2H); APCI MSm/z 394 [M+H]⁺.

EXAMPLE 2202-(4-((2-(3-Chlorophenyl)-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide

Following General Procedure A2,4-chloro-2-(3-chlorophenyl)-6-(trifluoromethyl)pyrimidine (0.100 g, 0.34mmol) was reacted with 2-(4-aminophenyl)acetamide (0.103 g, 0.68 mmol)to afford the title compound (0.042 g, 56%) as an off-white solid.MW=406.79. ¹H NMR (DMSO-d₆, 500 MHz) δ 10.24 (s, 1H), 8.33-8.25 (m, 2H),7.74-7.58 (m, 4H), 7.33 (d, J=8.5 Hz, 2H), 7.09 (s, 1H), 6.88 (s, 1H),3.39 (s, 2H), 2.70 (s, 1H); APCI MS m/z 407 [M+H]⁺.

EXAMPLE 2212-(4-((2-Cyclopentyl-6-ethylpyrimidin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of ethyl cyclopentanecarbimidate

A solution of cyclopentanecarbonitrile (10.0 g, 105.1 mmol) in EtOH (7mL) was treated with HCl (4.0 M in dioxane, 105 mL, 3.02 mol) and themixture stirred at rt overnight. After this time, nitrogen gas waspassed through the mixture and the mixture was concentrated. The residuewas treated with ether and reconcentrated. The residue was againsuspended in ether and filtered to afford the title compound (16.0 g,crude) as a white solid. MW=141.21. ¹H NMR (CDCl₃, 500 MHz) δ 4.79-4.46(m, 2H), 3.43-3.23 (m, 1H), 2.76 (s, 1H), 2.20-2.00 (m, 2H), 1.86-1.63(m, 6H), 1.55-1.40 (m, 3H); APCI MS m/z 142 [M+H]⁺.

Step 2. Preparation of cyclopentanecarboximidamide

A solution of ethyl cyclopentanecarbimidate (16.0 g, 113.4 mmol) inammonia (7.0 N in methanol, 125 mL) was stirred at rt for 48 h. Afterthis time, nitrogen gas was passed through the mixture and the reactionwas concentrated to afford the title compound (14.4 g, crude) as anoff-white gum. MW=112.17. ¹H NMR (CD₃OD, 500 MHz) δ 2.94-2.80 (m, 1H),2.16-1.99 (m, 2H), 1.91-1.79 (m, 2H), 1.78-1.64 (m, 4H); APCI MS m/z 113[M+H]⁺.

Step 3. Preparation of 2-cyclopentyl-6-ethylpyrimidin-4(3H)-one

A solution of cyclopentanecarboximidamide (8.5 g, 75.8 mmol) in ethanol(150 mL) was treated with ethyl propionaylacetate (13.7 g, 94.7 mmol),followed by the addition of sodium methoxide (4.9 g, 90.9 mmol). Themixture was then heated to 85° C. overnight. After this time, themixture was cooled and concentrated to a volume of approximately 50 mL.Then, 2M HCl in EtOH (68 mL) was added slowly. The resulting precipitatewas filtered, washed with water and ether, and the residue was dried ona high vacuum overnight to afford the title compound (8.9 g, crude) as apink solid. MW=192.26. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.00 (s, 1H), 6.14(s, 1H), 3.01 (quin, J=8.0 Hz, 1H), 2.55 (q, J=7.5 Hz, 2H), 2.13-2.01(m, 2H), 1.94-1.77 (m, 4H), 1.74-1.63 (m, 2H), 1.22 (t, J=7.5 Hz, 3H);APCI MS m/z 193 [M+H]⁺.

Step 4. Preparation of 4-chloro-2-cyclopentyl-6-ethylpyrimidine

Phosphorus(V) oxychloride (150 g, 99.0 mmol) was slowly added to2-cyclopentyl-6-ethylpyrimidin-4(3H)-one (18.9 g, 98.3 mmol) at 0° C.Then, the reaction mixture was warmed to 100° C. for 3 h. After thistime, the mixture was cooled, diluted with sodium hydroxide, andextracted with ethyl acetate. The combined organic layer was dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,hexanes/dichloromethane) to afford the title compound (5.1 g, 57%) asyellow oil. MW=210.70. ¹H NMR (CDCl₃, 300 MHz) δ 7.01 (s, 1H), 3.36-3.20(m, 1H), 2.74 (q, J=7.5 Hz, 2H), 2.14-1.99 (m, 2H), 1.98-1.76 (m, 4H),1.75-1.63 (m, 2H), 1.29 (t, J=7.5 Hz, 3H); APCI MS m/z 211 [M+H]⁺.

EXAMPLE 2212-(4-((2-Cyclopentyl-6-ethylpyrimidin-4-yl)amino)phenyl)acetamide

Following General Procedure A2, 4-chloro-2-cyclopentyl-6-ethylpyrimidine(0.100 g, 0.47 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.086g, 0.57 mmol) to afford the title compound (0.097 g, 97%) as a tansolid. MW=324.42. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.18 (s, 1H), 11.23 (s,1H), 7.64 (s, 1H), 7.49 (s, 1H), 7.36-7.25 (m, 2H), 6.88 (s, 1H), 6.76(s, 1H), 3.37 (d, J=7.5 Hz, 3H), 2.82-2.66 (m, 2H), 2.13-1.98 (m, 2H),1.94-1.73 (m, 4H), 1.72-1.59 (m, 2H), 1.25 (s, 3H); APCI MS m/z 325[M+H]⁺.

EXAMPLE 2222-(4-((2-Cyclopentyl-6-ethylpyrimidin-4-yl)amino)phenyl)ethanol

Following General Procedure A2, 4-chloro-2-cyclopentyl-6-ethylpyrimidine(0.100 g, 0.47 mmol) was reacted with 4-aminophenethyl alcohol (0.078 g,0.57 mmol) to afford the title compound (0.092 g, 92%) as an off-whitesolid. MW=311.42. ¹H NMR (DMSO-d₆, 500 MHz) δ 14.15 (s, 1H), 11.14 (s,1H), 7.62 (s, 1H), 7.34-7.17 (m, 2H), 6.75 (s, 1H), 4.63 (s, 1H), 3.61(t, J=6.9 Hz, 2H), 2.80-2.67 (m, 4H), 2.12-2.00 (m, 2H), 1.93-1.73 (m,4H), 1.71-1.58 (m, 2H), 1.24 (s, 3H); APCI MS m/z 312 [M+H]⁺.

EXAMPLE 223 Methyl2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate

A mixture of 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.275 g, 0.95mmol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.200 g, 0.95 mmol), Pd(dppf)Cl₂ (0.078 g, 0.095 mmol), and powderedNa₂CO₃ (0.302 g, 2.85 mmol) in dioxane (5 mL) and water (3 mL) wasstirred under an argon atmosphere at 90° C. for 48 h. After this time,the mixture was cooled and filtered through celite washing with ethylacetate. The filtrate was washed with brine (3×15 mL), dried over sodiumsulfate, filtered, and concentrated. The residue was purified by columnchromatography (silica, hexane/ethyl acetate) to afford the titlecompound (0.027 g, 14%) as a brown oil. MW=338.44. ¹H NMR (DMSO-d₆, 500MHz) δ 7.28-7.22 (m, 2H), 7.21-7.17 (m, 2H), 7.01 (s, 1H), 3.96 (s, 2H),3.63 (s, 2H), 3.59 (s, 3H), 3.21 (quin, J=8.1 Hz, 1H), 2.63 (q, J=7.6Hz, 2H), 2.01-1.90 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.70 (m, 2H),1.69-1.57 (m, 2H), 1.17 (t, J=7.6 Hz, 3H); APCI MS m/z 339 [M+H]⁺.

EXAMPLE 2242-(4-((2-Cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetic acid

A mixture of 4-chloro-2-cyclopentyl-6-ethylpyrimidine (0.200 g, 0.95mmol), methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate0. (275 g, 0.95 mmol), Pd(dppf)Cl₂ (0.078 g, 0.095 mmol), and powderedNa₂CO₃ (0.302 g, 2.85 mmol) in dioxane (5 mL) and water (3 mL) wasstirred under argon at 90° C. for 24 h. After this time, the mixture wascooled and filtered through celite washing with ethyl acetate. Thefiltrate was washed with brieme (3×15 mL), dried over sodium sulfate,filtered, and concentrated. The residue was purified by columnchromatography (silica, dichloromethane/methanol) to afford the titlecompound (0.121 g, 61%) as a brown oil. MW=324.42. ¹H NMR (DMSO-d₆, 500MHz) δ 12.26 (s, 1H), 7.25-7.18 (m, 4H), 7.01 (s, 1H), 3.95 (s, 2H),3.51 (s, 2H), 3.22 (t, J=8.1 Hz, 1H), 2.67-2.59 (m, 2H), 2.01-1.92 (m,2H), 1.88-1.71 (m, 4H), 1.67-1.58 (m, 2H) 1.17 (t, J=7.6 Hz, 3H); APCIMS m/z 325 [M+H]⁺.

EXAMPLE 2252-(4-((2-Cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)ethanol

A solution of2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetic acid(0.050 g, 0.15 mmol) in THF (5 mL) at rt under a nitrogen atmosphere wastreated with BH₃.SMe₂ (0.047 g, 0.62 mmol) and the mixture was heated at55° C. for 4 h. After this time, the mixture was cooled, diluted withmethanol, and concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the titlecompound (0.013 g, 30%) as a yellow oil. MW=310.43. ¹H NMR (DMSO-d₆, 500MHz) δ 7.22-7.17 (m, 2H), 7.16-7.11 (m, 2H), 7.00 (s, 1H), 4.58 (t,J=5.2 Hz, 1H), 3.93 (s, 2H), 3.60-3.53 (m, 2H), 3.21 (quin, J=8.1 Hz,1H), 2.71-2.58 (m, 4H), 2.01-1.91 (m, 2H), 1.88-1.79 (m, 2H), 1.78-1.69(m, 2H), 1.67-1.57 (m, 2H), 1.16 (t, J=7.6 Hz, 3H); APCI MS m/z 311[M+H]⁺.

EXAMPLE 2262-(4-((2-Cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetamide

A mixture of ammonia (7.0 N in methanol, 4 mL) and methyl2-(4-((2-cyclopentyl-6-ethylpyrimidin-4-yl)methyl)phenyl)acetate (0.067g, 0.20 mmol) and heated at 100° C. for 48 h. After this time, themixture was cooled and filtered through celite with ethyl acetatewashings. The filtrate was washed with brine (3×15 mL), dried oversodium sulfate, filtered, and concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.039 g, 59%) as a white solid. MW=323.43. ¹H NMR(DMSO-d₆, 500 MHz) δ 7.44 (s, 1H), 7.27-7.11 (m, 4H), 7.01 (s, 1H), 6.86(s, 1H), 3.95 (s, 2H) 3.31 (s, 2H), 3.29-3.14 (m, 1H), 2.62 (q, J=7.6Hz, 2H), 2.06-1.91 (m, 2H), 1.90-1.67 (m, 4H), 1.66-1.53 (m, 2H), 1.16(t, J=7.6 Hz, 3H); APCI MS m/z 324 [M+H]⁺.

EXAMPLE 2272-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of 2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-ol

To a solution of cyclopentanecarboximidamide (3.0 g, 27.1 mmol) inethanol (100 mL) was added ethyl 4,4,4-trifluoro-3-oxobutanoate (5.0 g,27.1 mmol) and sodium methoxide (1.76 g, 32.5 mmol). The mixture wasstirred at 85° C. for 16 h. After this time, the mixture wasconcentrated, diluted with ethanol (10 mL), and the suspension waschilled to 0° C. HCl (2M, 50 mL) was added and the suspension wasfiltered and washed with water. The solid was dried under heat andvacuum to afford the title compound (2.24 g, 36%) as a white solid.MW=232.20. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.96 (s, 1H), 6.67 (s, 1H), 3.03(quin, J=8.2 Hz, 1H), 2.00-1.92 (m, 2H), 1.83-1.67 (m, 4H), 1.64-1.53(m, 2H); APCI MS m/z 233 [M+H]⁺.

Step 2. Preparation of4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine

2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-ol (2.2 g, 9.47 mmol) wassuspended in POCl₃ (8.8 ml, 94.7 mmol) and heated to 75° C. for 2 h.After this time, the mixture was added to a chilled sodium hydroxidesolution (1 M) and then extracted with ethyl acetate. The organic layerwere dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate) to afford the title compound (2.1 g, 90%) as aclear oil. MW=250.65. ¹H NMR (CDCl₃, 500 MHz) δ 7.46 (s, 1H), 3.42(quin, J=8.2 Hz, 1H), 2.18-2.07 (m, 2H), 1.99-1.80 (m, 4H), 1.76-1.66(m, 2H); APCI MS m/z 251 [M+H]⁺.

EXAMPLE 2272-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)ethanol

Following general procedure A1,4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.100 g, 0.40mmol) was reacted with 2-(4-aminophenyl)ethanol (0.066 g, 0.48 mmol) toafford the title compound (0.097 g, 69%) as a white solid. MW=351.37. ¹HNMR (DMSO-d₆, 500 MHz) δ 9.93 (s, 1H), 7.68-7.54 (m, 2H), 7.21 (d, J=8.5Hz, 2H), 6.92 (s, 1H), 4.61 (t, J=5.0 Hz, 1H), 3.63-3.56 (m, 2H), 3.19(quin, J=8.0 Hz, 1H), 2.70 (t, J=7.0 Hz, 2H), 2.05-1.96 (m, 2H),1.89-1.60 (m, 6H); APCI MS m/z 352 [M+H]⁺.

EXAMPLE 2282-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedureA1,4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.100 g, 0.40mmol) was reacted with 2-(4-aminophenyl)acetamide (0.072 g, 0.48 mmol)to afford the title compound (0.095 g, 65%) as a white solid. MW=364.36.¹H NMR (DMSO-d₆, 500 MHz) δ 9.97 (s, 1H), 7.69-7.57 (m, 2H), 7.42 (s,1H), 7.25 (d, J=8.0 Hz, 2H), 6.93 (s, 1H), 6.85 (s, 1H), 3.34 (s, 2H),3.20 (quin, J=8.0 Hz, 1H), 2.05-1.97 (m, 2H), 1.89-1.59 (m, 6H); APCI MSm/z 365 [M+H]⁺.

EXAMPLE 2292-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)aceticacid

Step 1. Preparation of methyl2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate

Following general procedure G,4-chloro-2-cyclopentyl-6-(trifluoromethyl)pyrimidine (0.245 g, 0.98mmol) was reacted with methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.284 g, 0.98 mmol) to afford crude product (0.179 g) as an oil.MW=378.39. ¹H NMR (CDCl₃, 500 MHz) δ 7.26-7.22 (m, 4H), 7.16 (s, 1H),4.13 (s, 2H), 3.70 (s, 3H), 3.62 (s, 2H), 3.42 (quin, J=8.2 Hz, 1H),2.15-2.07 (m, 2H), 2.00-1.80 (m, 4H), 1.76-1.65 (m, 2H); APCI MS m/z 379[M+H]⁺.

EXAMPLE 2292-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)aceticacid

Following general procedure D, methyl2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate(0.55 mmol) was reacted with lithium hydroxide (0.055 g) to afford thetitle compound (0.051 g, 25% over two steps) as a light yellow oil.MW=364.36. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.27 (s, 1H), 7.72 (s, 1H), 7.28(d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 4.17 (s, 2H), 3.52 (s, 2H),3.41-3.33 (m, 1H), 2.08-1.99 (m, 2H), 1.89-1.60 (m, 6H); APCI MS m/z 365[M+H]⁺.

EXAMPLE 2302-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetamide

To a solution of2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)aceticacid (0.045 g, 0.12 mmol) in DMF (2 mL) was added EDC (0.047 g, 0.24mmol), HOBT (0.033 g, 0.24 mmol) and 7N ammonia in methanol (0.17 mL,1.2 mmol). The mixture was sealed and stirred at 85° C. for 3 h. Afterthis time, the mixture was diluted with ethyl acetate and then washedwith water. The organic layer were dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.034 g, 79%) as a white solid. MW=363.38. ¹H NMR(DMSO-d₆, 500 MHz) δ 7.71 (s, 1H), 7.41 (s, 1H), 7.26 (d, J=8.0 Hz, 2H),7.20 (d, J=8.0 Hz, 2H), 6.83 (s, 1H), 4.16 (s, 2H), 3.41-3.33 (m, 1H),3.33 (s, 2H), 2.09-1.99 (m, 2H), 1.89-1.61 (m, 6H); APCI MS m/z 364[M+H]⁺.

EXAMPLE 2312-(4-((2-Cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)ethanol

Following general procedure E1, methyl2-(4-((2-cyclopentyl-6-(trifluoromethyl)pyrimidin-4-yl)methyl)phenyl)acetate(0.079 g, 0.21 mmol) was reacted with DIBAL (1.0 M, 1.0 mL, 1.0 mmol) toafford the title compound (0.061 g, 83%) as a light yellow oil.MW=350.38. ¹H NMR (DMSO-d₆, 500 MHz) δ 7.70 (s, 1H), 7.23 (d, J=8.0 Hz,2H), 7.16 (d, J=8.0 Hz, 2H), 4.58 (t, J=5.5 Hz, 1H), 4.15 (s, 2H),3.41-3.33 (m, 1H), 2.68 (t, J=7.0 Hz, 2H), 2.09-1.99 (m, 2H), 1.90-1.61(m, 6H); APCI MS m/z 351 [M+H]⁺.

EXAMPLE 2322-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of4-chloro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.250g, 1.32 mmol) and sodium thiomethoxide (0.093 g, 1.32 mmol) in THF (10mL) was stirred at rt for 6 h. After this time, the mixture was dilutedwith saturated aqueous sodium bicarbonate and extracted with ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate, filtered and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.210 g, 84%) as an off-white solid.MW=200.69. ¹H NMR (DMSO-d₆, 300 MHz) δ 2.90 (t, J=7.6 Hz, 2H), 2.71 (t,J=7.6 Hz, 2H), 2.56 (s, 3H), 2.10 (quin, J=7.6 Hz, 2H); APCI MS m/z 201[M+H]⁺.

Step 2. Preparation of4-chloro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

To a solution of4-chloro-2-(methylthio)-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.208 g,1.04 mmol) in methylene chloride (4 mL) was added m-CPBA (0.805 g, 4.66mmol) in portions over a 15 min period at 0° C. and then the mixture wasslowly warmed to rt and stirred overnight. After this time, the reactionmixture was diluted with water and extracted with ethyl acetate. Thecombined organic layer was dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated to afford the title compound(0.157 g, 75%). MW=232.69. ¹H NMR (CDCl₃, 300 MHz) δ 3.39-3.28 (m, 5H),3.11 (t, J=7.6 Hz, 2H), 2.27 (t, J=7.6 Hz, 2H); APCI MS m/z 233 [M+H]⁺.

Step 3. Preparation of4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine

To a solution of cyclopentanol (0.287 g, 3.33 mmol) in THF (5 mL) wasadded sodium hydride (0.016 g, 0.67 mmol) and the mixture stirred at rtunder a nitrogen atmosphere for 30 min. Then, the mixture was addedtreated with a solution of4-chloro-2-(methylsulfonyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.155 g, 0.67 mmol) dropwise in THF (2 mL) and the resulting mixturestirred at rt for 2 h. After this time, the reaction mixture was dilutedwith water and extracted with ethyl acetate. The combined organic layerwas dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/dichloromethane) to afford the title compound (0.080 g, 52%).MW=238.71. ¹H NMR (CD₃OD, 300 MHz) δ 5.64-5.40 (m, 1H), 2.90 (t, J=7.6Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 2.21-2.08 (m, 2H), 1.90-1.71 (m, 4H),1.71-1.59 (m, 2H), 1.38-1.18 (m, 2H); APCI MS m/z 239 [M+H]⁺.

Step 4. Preparation of ethyl2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetate

Following General Procedure B2,4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.075 g, 0.31 mmol) was reacted with 4-aminophenylacetic acid ethylester (0.084 g, 0.47 mmol) to afford the title compound (0.110 g, crude)as a white solid. MW=381.47. ¹H NMR (CD₃OD, 300 MHz) δ 7.61 (d, J=8.6Hz, 2H), 7.18 (d, J=8.6 Hz, 2H), 5.55-5.45 (m, 1H), 4.13 (q, J=7.6 Hz,2H), 3.57 (s, 2H), 2.79 (t, J=7.6 Hz, 2H), 2.71 (t, J=7.6 Hz, 2H),2.14-1.95 (m, 4H), 1.89 (s, 1H), 1.87-1.76 (m, 4H), 1.72-1.61 (m, 2H),1.24 (t, J=7.1 Hz, 1H); APCI MS m/z 382 [M+H]⁺.

EXAMPLE 2322-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetamide

Following General Procedure C, ethyl2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)acetate(0.100 g, 0.26 mmol) was reacted with ammonia in methanol (7.0 M, 4 mL)to afford the title compound (0.030 g, 30%) as a brown solid. MW=352.43.¹H NMR (DMSO-d₆, 300 MHz) δ 9.28 (s, 1H), 7.66 (d, J=8.6 Hz, 2H), 7.37(s, 1H), 7.13 (d, J=8.6 Hz, 2H), 6.83 (s, 1H), 5.56-540 (m, 1H), 3.28(s, 2H), 2.74 (t, J=7.6 Hz, 2H), 2.64 (t, J=7.6 Hz, 2H), 2.07-1.91 (m,4H), 1.82-1.69 (m, 4H), 1.69-1.56 (m, 2H); APCI MS m/z 353 [M+H]⁺.

EXAMPLE 233 22-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)phenyl)ethanol

Following General Procedure B1,4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidine(0.200 g, 0.84 mmol), dioxane (3 mL) was reacted with 4-aminophenethylalcohol (0.172 g, 1.26 mmol) to afford the title compound (0.044 g, 22%)as a white solid. MW=339.43. ¹H NMR (DMSO-d₆, 300 MHz) δ 9.23 (s, 1H),7.64 (d, J=8.4 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 5.49-5.40 (m, 1H),3.65-3.50 (m, 2H), 2.73 (t, J=7.6 Hz, 2H) 2.69-5.59 (m, 5H), 2.09-1.90(m, 4H), 1.80-1.53 (m, 6H); APCI MS m/z 340 [M+H]⁺.

EXAMPLE 2342-(4-((2-(3-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one

A solution of 3-chlorobenzimidamide (5 g, 32.34 mmol) in ethanol (90 mL)was treated with ethyl-2-cyclohexaneonecarboxylate (6.3 g, 40.43 mmol)and sodium methoxide (2.1 g, 38.81 mmol). The reaction mixture washeated at 85° C. for 18 h. After this time, the reaction mixture wascooled and concentrated to a volume of approximately 50 mL. Then, 2.0 MHCl (68 mL) was added slowly. The resulting precipitate was filtered,washed with water and ether, and the residue was dried on a high vacuumovernight to afford the title compound (2.2 g, crude) as a light yellowsolid. MW=260.72. ¹H NMR (DMSO-d₆, 300 MHz) δ 12.64 (s, 1H), 8.16-8.10(m, 1H), 8.08-7.99 (m, 1H), 7.66-7.57 (m, 1H), 7.54 (t, J=7.9 Hz, 1H),2.66-2.55 (m, 2H), 2.44-2.33 (m, 2H), 1.84-1.61 (m, 4H); APCI MS m/z 261[M+H]⁺.

Step 2. Preparation of4-chloro-2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazoline

Phosphorus(V) oxychloride (17.6 g, 114.7 mmol) was slowly added to2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4(3H)-one (2.2 g, 8.5mmol) at 0° C. The reaction mixture was warmed to 100° C. and held atthat temperature for 2 h. After this time, the mixture was cooled,quenched with saturated sodium hydroxide, and extracted with ethylacetate. The combined organic layer was dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, hexanes/dichloromethane) toafford the title compound (2.1 g, 23%) as a white solid. MW=279.16. ¹HNMR (CDCl₃, 300 MHz) δ 8.43-8.37 (m, 1H), 8.32-8.24 (m, 1H), 7.49-7.33(m, 2H), 3.03-2.87 (m, 2H), 2.86-2.70 (m, 2H), 1.98-1.83 (m, 4H); APCIMS m/z 279 [M+H]⁺.

EXAMPLE 2342-(4-((2-(Cyclopent-1-en-1-yl)-6-(trifluoromethyl)pyridin-4-yl)amino)phenyl)aceticacid

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (0.100 g, 0.36mmol) was reacted with 2-(4-aminophenyl)acetamide (0.065 g, 0.43 mmol)and the reaction mixture was stirred at 80° C. for 18 h. After thistime, the reaction mixture was cooled, diluted with water, and extractedwith ethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by column chromatography (silica, dichloromethane/methanol)to afford the title compound (0.103 g, 100%) as a white solid.MW=392.88. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.42 (s, 1H), 8.27-8.16 (m, 2H),7.73-7.64 (m, 2H), 7.55-7.45 (m, 3H), 7.26 (d, J=8.5 Hz, 2H), 6.90 (s,1H), 3.36 (s, 2H) 2.79-2.70 (m, 2H), 2.66-2.56 (m, 2H), 1.83 (s, 4H);APCI MS m/z 393 [M+H]⁺.

EXAMPLE 2352-(4-((2-(3-Chlorophenyl)-5,6,7,8-tetrahydroquinazolin-4-yl)amino)phenyl)ethanol

Following General Procedure A1,4-chloro-2-(3-chlorophenyl)-5,6,7,8-tetrahydroquinazoline (0.100 g, 0.36mmol) was reacted with 4-aminophenethyl alcohol (0.059 g, 0.43 mmol) toafford the title compound (0.101 g, 100%) as a yellow solid. MW=379.88.¹H NMR (DMSO-d₆, 300 MHz) δ 8.35 (s, 1H), 8.25-8.16 (m, 2H), 7.69-7.64(m, 2H), 7.52-7.47 (m, 2H), 7.22 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.2 Hz,1H), 3.66-3.58 (m, 2H), 2.78-2.68 (m, 4H), 2.63-2.57 (m, 2H), 1.89-1.77(m, 4H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 2362-(4-((2-(Pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following general procedure B1,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol)was reacted with pyrrolidine (0.085 g, 1.2 mmol) to afford the titlecompound (0.069 g, 38%) as a light yellow solid. MW=222.71. ¹H NMR(CDCl₃, 300 MHz) δ 6.13 (s, 1H), 3.46-3.36 (m, 4H), 2.97-2.81 (m, 4H),2.13-1.94 (6H); APCI MS m/z 223 [M+H]⁺.

Step 2. Preparation of ethyl2-(4-((2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.068g, 0.30 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.080 g,0.45 mmol) to afford the title compound (0.100 g, 90%) as a brown oil.MW=365.47. APCI MS m/z 366 [M+H]⁺.

EXAMPLE 2362-(4-((2-(Pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.100 g, 0.27 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.039 g, 39%) as a light yellow solid. MW=372.89. ¹H NMR(DMSO-d₆, 500 MHz) δ 12.00 (s, 1H), 8.97 (s, 1H), 7.52 (s, 1H), 7.32 (d,J=8.5 Hz, 2H), 7.28 (d, J=8.5 Hz, 2H), 6.90 (s, 1H), 5.77-5.75 (m, 1H),3.40 (s, 2H), 3.37-3.31 (m, 4H), 2.97 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.5Hz, 2H), 2.13 (quin, J=7.5 Hz, 2H), 1.98-1.91 (m, 4H); APCI MS m/z 337[M+H]⁺.

EXAMPLE 237 Methyl2-(4-((2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetatehydrochloride

Following general procedure C, ethyl2-(4-((2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.100 g, 0.27 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL).Formation of the amide[2-(4-((2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide]was the major product and formation of the ester [methyl2-(4-((2-(pyrrolidin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate]was minor. Chromatography, followed by formation of the hydrochloridesalt, gave the methyl ester product (0.020 g, 19%) as a light yellowsolid. MW=387.90. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.04 (s, 1H), 8.98 (s,1H), 7.37-7.29 (m, 4H), 5.77 (s, 1H), 3.71 (s, 2H), 3.63 (s, 3H),3.38-3.33 (m, 4H), 2.98 (t, J=7.5 Hz, 2H), 2.77 (t, J=7.5 Hz, 2H), 2.13(quin, J=7.5 Hz, 2H), 1.98-1.92 (m, 4H); APCI MS m/z 352 [M+H]⁺.

EXAMPLE 2382-(4-((2-(Piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Step 1. Preparation of tert-butyl4-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate

Following general procedure B1,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol)was reacted with tert-butyl piperazine-1-carboxylate (0.223 g, 1.2 mmol)to afford the title compound (0.052 g, 19%) as a yellow solid.MW=337.84. ¹H NMR (CDCl₃, 500 MHz) δ 6.39 (s, 1H), 3.56-3.50 (m, 4H),3.49-3.44 (m, 4H), 2.92 (t, J=7.5 Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.08(quin, J=7.5 Hz, 2H), 1.48 (s, 9H); APCI MS m/z 338[M+H]⁺.

Step 2. Preparation of tert-butyl4-(4-((4-(2-hydroxyethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate

Following general procedure B1, tert-butyl4-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate(0.050 g, 0.15 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.030 g,0.22 mmol) to afford the title compound (0.026 g, 40%) as an orange oil.MW=438.56. APCI MS m/z 439 [M+H]⁺.

EXAMPLE 2382-(4-((2-(Piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

To a solution of tert-butyl4-(4-((4-(2-hydroxyethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate(0.026 g, 0.059 mmol) in methylene chloride (5 mL) was added TFA (0.1mL). The mixture stirred at rt for 16 h and purified by preparative HPLC(water/acetonitrile with 0.05% TFA), followed by formation of thehydrochloride salt to afford the title compound (0.010 g, 41%) as ayellow-brown solid. MW=411.37. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.21 (s,1H), 9.46-9.19 (m, 3H), 7.31 (d, J=8.0 Hz, 2H), 7.25 (d, J=8.0 Hz, 2H),6.04 (s, 1H), 3.68-3.56 (m, 6H), 3.20 (br s, 4H), 3.05-2.96 (m, 2H),2.81-2.72 (m, 4H), 2.19-2.10 (m, 2H); APCI MS m/z 339 [M+H]⁺.

EXAMPLE 2392-(4-((2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Step 1. Preparation of4-chloro-2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine(0.130 g, 0.69 mmol) in dioxane (3 mL) was addedtributyl(furan-2-yl)stannane (0.271 g, 0.76 mmol) andtetrakis(triphenylphosphine)palladium (0.039 g, 0.035 mmol). The mixturewas purged with nitrogen and then heated to 110° C. under sealedconditions for 2 h. After this time, the mixture was diluted with waterand extracted with ethyl acetate. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate) to afford the title compound (0.140 g, 92%) as a white solid.MW=219.67. ¹H NMR (CDCl₃, 500 MHz) δ 7.52-7.48 (m, 1H), 7.45 (s, 1H),7.02-6.98 (m, 1H), 6.52-6.48 (m, 1H), 3.10 (t, J=7.5 Hz, 2H), 2.99 (t,J=7.5 Hz, 2H), 2.15 (quin, J=7.5 Hz, 2H); APCI MS m/z 220 [M+H]⁺.

EXAMPLE 2392-(4-((2-(Furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure B1,4-chloro-2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.064 g,0.29 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.048 g, 0.35mmol), followed by formation of the hydrochloride salt to afford thetitle compound (0.038 g, 37%) as a white solid. MW=356.85. ¹H NMR(DMSO-d₆, 500 MHz) δ 14.14 (s, 1H), 9.57 (s, 1H), 7.95 (s, 1H), 7.52 (s,1H), 7.35 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.5 Hz, 2H), 7.01 (s, 1H),6.77-6.72 (m, 1H), 4.68 (s, 1H), 3.66 (t, J=7.0 Hz, 2H), 3.11 (t, J=7.5Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.78 (t, J=7.0 Hz, 2H), 2.20 (quin,J=7.5 Hz, 2H); APCI MS m/z 321 [M+H]⁺.

EXAMPLE 2402-(4-((2-(Furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(4-((2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.064 g,0.29 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.073 g,0.41 mmol) to afford the title compound (0.075 g, 61%) as a white foam.MW=362.42. ¹H NMR (CDCl₃, 500 MHz) δ 7.45-4.43 (m, 1H), 7.30 (d, J=8.5Hz, 2H), 7.24 (s, 1H), 7.18 (d, J=8.5 Hz, 2H), 6.93-6.89 (m, 1H),6.48-6.44 (m, 1H), 5.73 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.62 (s, 2H),3.05 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz,2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 363 [M+H]⁺.

EXAMPLE 2402-(4-((2-(Furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-(furan-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.075 g, 0.21 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.039 g, 51%) as a light yellow solid. MW=369.85. ¹H NMR(DMSO-d₆, 500 MHz) δ 14.21 (s, 1H), 9.78 (s, 1H), 8.01-7.98 (m, 1H),7.64 (d, J=3.5 Hz, 1H), 7.56 (s, 1H), 7.40 (d, J=8.5 Hz, 2H), 7.32 (d,J=8.5 Hz, 2H), 7.02 (s, 1H), 6.93 (s, 1H), 6.79-6.75 (m, 1H), 3.45 (s,2H), 3.15 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.22 (quin, J=7.5Hz, 2H); APCI MS m/z 334 [M+H]⁺.

EXAMPLE 2412-(4-((2-(Oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine(0.152 g, 0.81 mmol) in dioxane (3 mL) was added2-(tributylstannyl)oxazole (0.318 g, 0.89 mmol) andtetrakis(triphenylphosphine)palladium (0.046 g, 0.040 mmol). The mixturewas purged with nitrogen and then heated to 110° C. under sealedconditions for 16 h. After this time, the mixture was diluted with waterand extracted with ethyl acetate. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate) to afford the title compound (0.061 g, 34%) as a white solid.MW=220.66. ¹H NMR (CDCl₃, 500 MHz) δ 7.94 (s, 1H), 7.78 (s, 1H), 7.29(s, 1H), 3.19 (t, J=7.5 Hz, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.22 (quin,J=7.5 Hz, 2H); APCI MS m/z 221 [M+H]⁺.

EXAMPLE 2412-(4-((2-(Oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol

Following general procedure B1,2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole (0.059 g,0.27 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.044 g, 0.32mmol) to afford the title compound (0.049 g, 57%) as a light yellowsolid. MW=321.37. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.19-8.14 (m, 2H), 7.45(s, 1H), 7.30-7.28 (m, 1H), 7.24 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz,2H), 4.64 (s, 1H), 3.66-3.59 (m, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.84 (t,J=7.0 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 2.09 (quin, J=7.5 Hz, 2H); APCIMS m/z 322 [M+H]⁺.

EXAMPLE 2422-(4-((2-(Oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of ethyl2-(4-((2-(oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following genera procedure B1,2-(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)oxazole (0.040 g,0.18 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.039 g,0.22 mmol) to afford the title compound (0.047 g, 71%) as a white foam.MW=363.41. ¹H NMR (CDCl₃, 500 MHz) δ7.72 (s, 1H), 7.66 (s, 1H), 7.31 (d,J=8.5 Hz, 2H), 7.22-7.17 (m, 3H), 5.80 (s, 1H), 4.18 (q, J=7.0 Hz, 2H),3.61 (s, 2H), 3.11 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.22(quin, J=7.5 Hz, 2H), 1.28 (t, J=7.0 Hz, 3H); APCI MS m/z 364 [M+H]⁺.

EXAMPLE 2422-(4-((2-(Oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

Following general procedure C, ethyl2-(4-((2-(oxazol-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.047 g, 0.13 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL)to afford the title compound (0.027 g, 63%) as a white solid. MW=334.37.¹H NMR (DMSO-d₆, 500 MHz) δ 8.24 (s, 1H), 8.16 (s, 1H), 7.49-7.43 (m,2H), 7.32-7.25 (m, 3H), 7.17 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 3.37 (s,2H), 2.90 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5Hz, 2H); APCI MS m/z 335 [M+H]⁺.

EXAMPLE 243 22-(4-((2-(Thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following general procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol)was reacted with thiophen-3-ylboronic acid (0.112 g, 0.88 mmol) toafford the title compound (0.132 g, 70%) as a white solid. MW=235.73. ¹HNMR (CDCl₃, 500 MHz) δ 7.88-7.82 (m, 1H), 7.61-7.56 (m, 1H), 7.40-7.34(m, 1H), 3.11 (t, J=7.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.16 (quin,J=7.5 Hz, 2H); APCI MS m/z 236 [M+H]⁺.

EXAMPLE 243 22-(4-((2-(Thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol

Following general procedure B1,4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.060g, 0.25 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.041 g, 0.30mmol), followed by formation of the hydrochloride salt to afford thetitle compound (0.025 g, 27%) as a white solid. MW=356.85. MW=372.91. ¹HNMR (DMSO-d₆, 500 MHz) δ 13.91 (s, 1H), 9.68 (s, 1H), 8.37-8.32 (m, 1H),7.80-7.76 (m, 1H), 7.59-7.55 (m, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.30 (d,J=8.5 Hz, 2H), 7.03 (s, 1H), 4.67 (s, 1H), 3.65 (t, J=7.0 Hz, 2H), 3.15(t, J=7.5 Hz, 2H), 2.88 (t, J=7.0 Hz, 2H), 2.77 (t, J=7.0 Hz, 2H), 2.20(quin, J=7.5 Hz, 2H); APCI MS m/z 337 [M+H]⁺.

EXAMPLE 2442-(4-((2-(Thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of ethyl2-(4-((2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.070g, 0.30 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.064 g,0.36 mmol) to afford the title compound (0.065 g, 57%) as anorange-brown oil. MW=378.49. APCI MS m/z 379 [M+H]⁺.

EXAMPLE 2442-(4-((2-(Thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

Following general procedure C, ethyl2-(4-((2-(thiophen-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.065 g, 0.17 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.033 g, 50%) as a light yellow solid. MW=385.91. ¹H NMR(DMSO-d₆, 500 MHz) δ 13.84 (s, 1H), 9.69 (s, 1H), 8.35-8.31 (m, 1H),7.81-7.76 (m, 1H), 7.59-7.56 (m, 1H), 7.51 (s, 1H), 7.38 (d, J=8.5 Hz,2H), 7.33 (d, J=8.5 Hz, 2H), 7.05 (s, 1H), 6.92 (s, 1H), 3.43 (s, 2H),3.15 (t, J=7.5 Hz, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.23 (quin, J=7.5 Hz,2H); APCI MS m/z 350 [M+H]⁺.

EXAMPLE 2452-(4-((2-(5-Chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation4-chloro-2-(5-chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following general procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.150 g, 0.80 mmol)was reacted with (5-chlorothiophen-2-yl)boronic acid (0.142 g, 0.88mmol) to afford the title compound (0.031 g, 14%) as a white solid.MW=270.18. ¹H NMR (CDCl₃, 500 MHz) δ 7.32 (s, 1H), 7.27 (d, J=4.0 Hz,1H), 6.89 (d, J=4.0 Hz, 1H), 3.08 (t, J=7.5 Hz, 2H), 2.98 (t, J=7.5 Hz,2H), 2.16 (quin, J=7.5 Hz, 2H); APCI MS m/z 270 [M+H]⁺.

Step 2. Preparation of ethyl2-(4-((2-(5-chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-(5-chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.030 g, 0.11 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate(0.024 g, 0.13 mmol) to afford crude product (0.023 g) as an orange oil.MW=412.93. APCI MS m/z 413 [M+H]⁺.

EXAMPLE 2452-(4-((2-(5-Chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-(5-chlorothiophen-2-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.11 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL), followedby formation of the hydrochloride salt to afford the title compound(0.011 g, 24% over two steps) as a light yellow solid. MW=420.36. ¹H NMR(DMSO-d₆, 500 MHz) δ 14.09 (s, 1H), 9.64 (s, 1H), 7.74 (s, 1H), 7.51 (s,1H), 7.36 (d, J=8.5 Hz, 2H), 7.30-7.27 (m, 3H), 6.96-6.86 (m, 2H), 3.42(s, 2H), 3.14-3.05 (m, 2H), 2.89-2.82 (m, 2H), 2.23-2.13 (m, 2H); APCIMS m/z 384 [M+H]⁺.

EXAMPLE 2462-(4-((2-(Cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following general procedure F except the reaction was heated to 140° C.under microwave irradiation for 2 h,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.157 g, 0.84 mmol)was reacted with cyclopent-1-en-1-ylboronic acid (0.112 g, 1.0 mmol) toafford the title compound (0.120 g, 65%) as a white solid. MW=219.71. ¹HNMR (CDCl₃, 500 MHz) δ 7.06 (s, 1H), 6.62-6.57 (m, 1H), 3.06 (t, J=7.5Hz, 2H), 2.97 (t, J=7.5 Hz, 2H), 2.77-2.70 (m, 2H), 2.58-2.52 (m, 2H),2.13 (quin, J=7.5 Hz, 2H), 2.08-2.00 (m, 2H); APCI MS m/z 220 [M+H]⁺.

EXAMPLE 2462-(4-((2-(Cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure A2,4-chloro-2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.100 g, 0.45 mmol) was reacted with 2-(4-aminophenyl)acetamide (0.081g, 0.54 mmol), followed by formation of the hydrochloride salt to affordthe title compound (0.048 g, 29%) as a light yellow solid. MW=420.38. ¹HNMR (DMSO-d₆, 500 MHz) δ 13.47 (s, 1H), 9.69 (s, 1H), 7.52 (s, 1H), 7.37(d, J=8.5 Hz, 2H), 7.29 (d, J=8.5 Hz, 2H), 6.92-6.88 (m, 1H), 6.71-6.68(m, 1H), 3.42 (s, 2H), 3.12 (t, J=7.5 Hz, 2H), 2.85 (t, J=7.5 Hz, 2H),2.61-2.54 (m, 4H), 2.19 (quin, J=7.5 Hz, 2H), 1.95 (quin, J=7.5 Hz, 2H);APCI MS m/z 384 [M+H]⁺.

EXAMPLE 2472-(4-((2-Cyclopentyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

To a solution of2-(4-((2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride (0.042 g, 0.11 mmol) in ethanol (10 mL) was added 10%palladium on carbon (0.005 g). The mixture stirred at rt for 2 h underan atmosphere of hydrogen. After this time, the mixture was filteredover celite, concentrated, and the residue converted to thehydrochloride salt to afford the title compound (0.040 g, 95%) as awhite solid. MW=420.38. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.60 (s, 1H), 9.59(s, 1H), 7.52 (s, 1H), 7.36 (d, J=8.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H),6.92 (s, 1H), 6.69-6.66 (m, 1H), 3.42 (s, 1H), 3.18-3.04 (m, 3H), 2.83(t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 2.07-1.96 (m, 2H),1.77-1.69 (m, 2H), 1.68-1.52 (m, 4H), 1.37-1.22 (m, 2H); APCI MS m/z 384[M+H]⁺.

EXAMPLE 2482-(4-((2-(Cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure B1,4-chloro-2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine(0.095 g, 0.43 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.089 g,0.65 mmol), followed by formation of the hydrochloride salt to affordthe title compound (0.110 g, 79%) as a yellow solid. MW=356.89. ¹H NMR(DMSO-d₆, 500 MHz) δ 13.67 (s, 1H), 9.71 (s, 1H), 7.33 (d, J=8.5 Hz,2H), 7.26 (d, J=8.5 Hz, 2H), 6.99 (s, 1H), 6.66 (s, 1H), 3.64 (t, J=7.0Hz, 2H), 3.13 (t, J=7.5 Hz, 2H), 2.84 (t, J=7.5 Hz, 2H), 2.76 (t, J=7.0Hz, 2H), 2.56 (t, J=7.5 Hz, 4H), 2.18 (quin, J=7.5 Hz, 2H) 1.94 (quin,J=7.5 Hz, 2H); APCI MS m/z 321 [M+H]⁺.

EXAMPLE 2492-(4-((2-cyclopentyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

To a solution of2-(4-((2-(cyclopent-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanol(0.070 g, 0.22 mmol) in ethanol (10 mL) was added 10% palladium oncarbon (0.010 g) and the mixture was stirred at under an atmosphere ofhydrogen at rt for 3 h. After this time, the mixture was filtered overcelite, concentrated, purified by column chromatography (silica,dichloromethane/methanol) and followed by formation of the hydrochloridesalt to afford the title compound (0.053 g, 68%) as a white solid.MW=358.91. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.66 (s, 1H), 9.58 (s, 1H), 7.33(d, J=8.5 Hz, 2H), 7.23 (d, J=8.5 Hz, 2H), 6.65 (s, 1H), 4.67 (br s,1H), 3.65-3.63 (m, 2H), 3.15-3.04 (m, 3H), 2.82 (t, J=7.5 Hz, 2H), 2.76(t, J=7.0 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 2.06-1.96 (m, 2H),1.78-1.54 (m, 6H); APCI MS m/z 323 [M+H]⁺.

EXAMPLE 2502-(4-((2-Cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of4-chloro-2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine

Following general procedure F,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.157 g, 0.84 mmol)was reacted with cyclohex-1-en-1-ylboronic acid (0.142 g, 1.13 mmol) toafford crude product (0.130 g) as an oil. MW=233.74. ¹H NMR (CDCl₃, 500MHz) δ 7.13 (s, 1H), 7.08 (s, 1H), 6.70-6.66 (m, 1H), 3.06 (t, J=7.5 Hz,2H), 2.96 (t, J=7.5 Hz, 2H), 2.47-2.42 (m, 2H), 2.27-2.22 (m, 2H),2.17-2.09 (m, 2H), 1.82-1.75 (m, 2H), 1.69-1.63 (m, 2H); APCI MS m/z 234[M+H]⁺.

Step 2. Preparation of ethyl2-(4-((2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridine(1.03 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.150 g,0.84 mmol) to afford the title compound (0.121 g, 31% over two steps) asan orange oil. MW=376.49. APCI MS m/z 377 [M+H]⁺.

Step 3. Preparation of ethyl2-(4-((2-cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

To a solution of ethyl2-(4-((2-(cyclohex-1-en-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.120 g, 0.32 mmol) in ethanol (10 mL) was added 10% palladium oncarbon (0.020 g) and the mixture stirred at under an atmosphere ofhydrogen at rt for 16 h. After this time, the mixture was filtered overcelite, concentrated, and purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.130 g, 100%)as an off-white solid. MW=378.51. ¹H NMR (CD₃OD, 500 MHz) δ 7.17 (d,J=8.3 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.57-6.54 (m, 1H), 4.06 (q, J=7.0Hz, 2H), 3.53 (s, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.69 (t, J=7.5 Hz, 2H),2.45-2.36 (m, 1H), 2.02 (quin, J=7.5 Hz, 2H), 1.78-1.58 (m, 5H),1.33-1.13 (m, 8H); APCI MS m/z 379 [M+H]⁺.

EXAMPLE 2502-(4-((2-Cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.065 g, 0.17 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.023 g, 35%) as a white solid. MW=385.93. ¹H NMR (DMSO-d₆,300 MHz) δ 13.73 (s, 1H), 9.62 (s, 1H), 7.56 (s, 1H), 7.37 (d, J=8.4 Hz,2H), 7.26 (d, J=8.4 Hz, 2H), 6.94 (s, 1H), 6.65 (s, 1H), 3.42 (s, 2H),3.07 (t, J=7.5 Hz, 2H), 2.83 (t, J=7.5 Hz, 2H), 2.78-2.66 (m, 1H), 2.18(quin, J=7.5 Hz, 2H), 1.87-1.60 (m, 5H), 1.52-1.13 (m, 5H); APCI MS m/z350 [M+H]⁺.

EXAMPLE 2512-(4-((2-cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure E2, ethyl2-(4-((2-cyclohexyl-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.065 g, 0.17 mmol) was reacted with BH₃.DMS (10.0 M, 0.10 mL, 1.0mmol), followed by formation of the hydrochloride salt to afford thetitle compound (0.035 g, 55%) as a white solid. MW=372.93. ¹H NMR(DMSO-d₆, 300 MHz) δ 13.59 (s, 1H), 9.57 (s, 1H), 7.34 (d, J=8.5 Hz,2H), 7.23 (d, J=8.5 Hz, 2H), 6.63 (s, 1H), 4.73-4.63 (m, 1H), 3.71-3.59(m, 2H), 3.06 (t, J=7.5 Hz, 2H), 2.88-2.63 (m, 5H), 2.18 (quin, J=7.5Hz, 2H) 1.85-1.61 (m, 5H), 1.52-1.11 (m, 5H); APCI MS m/z 337 [M+H]⁺.

EXAMPLE 2522-(4-((2-(Piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

A microwave vessel was charged with a solution of2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine (0.165 g, 0.88 mmol)in ethanol (3 mL). p-Toluenesulfonic acid (0.167 g, 0.88 mmol) and ethyl2-(4-aminophenyl)acetate (0.157 g, 0.88 mmol) were added and the vesselwas sealed with an aluminum cap. The mixture was heated to 120° C. for 2d, cooled, diluted with satd. aq. sodium bicarbonate, and extracted withethyl acetate. The combined organic layer was dried over anhydroussodium sulfate, filtered, and the filtrate was concentrated. The residuewas purified by column chromatography (silica, hexanes/ethyl acetate) toafford the title compound (0.160 g, 55%) as an orange oil. MW=330.81. ¹HNMR (CDCl₃, 500 MHz) δ 7.33-7.28 (m, 2H) 7.16-7.12 (m, 2H), 6.74 (s,1H), 5.73 (s, 1H), 4.18 (q, J=7.0 Hz, 2H), 3.62 (s, 2H), 2.98 (t, J=7.5Hz, 2H), 2.76 (t, J=7.5 Hz, 2H), 2.18 (quin, J=7.5 Hz, 2H), 1.28 (t,J=7.0 Hz, 3H); APCI MS m/z 331 [M+H]⁺.

Step 2. Preparation of tert-butyl4-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate

Following general procedure B1, ethyl2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.110 g, 0.33 mmol) was reacted with tert-butylpiperazine-1-carboxylate (0.073 g, 0.40 mmol) to afford the titlecompound (0.034 g, 21%) as an orange foam. MW=480.59. ¹H NMR (CDCl₃, 500MHz) δ 7.27 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.17 (s, 1H),5.59 (s, 1H), 4.17 (q, J=7.0 Hz, 2H), 3.60 (s, 2H), 3.54-3.48 (m, 4H),3.40-3.34 (m, 4H), 2.89 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.12(quin, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.27 (t, J=7.0 Hz, 3H); APCI MS m/z481 [M+H]⁺.

Step 3. Preparation of tert-butyl4-(4-((4-(2-amino-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate

Following general procedure C, tert-butyl4-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylate(0.034 g, 0.071 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL)to afford crude product (0.031 g) as an orange oil. MW=451.56. APCI MSm/z 452 [M+H]⁺.

EXAMPLE 2522-(4-((2-(Piperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

To a solution of tert-butyl4-(4-((4-(2-amino-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)piperazine-1-carboxylatein methanol (3 mL) was added HCl (6 M, 0.1 mL). The mixture was heatedto 65° C. for 16 h. The Boc group was removed, however, the amidefunction was replaced with a methyl ester group. The mixture wasconcentrated and following general procedure C, desired product wasobtained after forming the hydrochloride salt (0.015 g, 50%) as anorange-brown solid. MW=424.37. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.26 (s,1H), 9.40-9.28 (m, 3H), 7.53 (s, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.29 (d,J=8.5 Hz, 2H), 6.91 (s, 1H), 6.07 (s, 1H), 3.64-3.57 (m, 4H), 3.41 (s,2H), 3.20 (br s, 4H), 3.02 (t, J=7.5 Hz, 2H), 2.78 (t, J=7.5 Hz, 2H),2.15 (quin, J=7.5 Hz, 2H); APCI MS m/z 352 [M+H]⁺.

EXAMPLE 2532-(4-((2-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(4-((2-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1, ethyl2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.095 g, 0.29 mmol) was reacted with 1-methylpiperazine (0.043 g, 0.44mmol) to afford the title compound (0.017 g, 15%) as an orange oil.MW=394.51. ¹H NMR (CD₃OD, 500 MHz) δ 7.15 (d, J=8.3 Hz, 2H), 7.07 (d,J=8.3 Hz, 2H), 6.07 (s, 1H), 4.05 (q, J=7.0 Hz, 2H), 3.51 (s, 2H), 2.72(t, J=7.5 Hz, 2H), 2.64 (t, J=7.5 Hz, 2H), 2.46-2.38 (m, 4H), 2.21 (s,3H), 1.99 (quin, J=7.5 Hz, 2H), 1.15 (t, J=7.0 Hz, 3H); APCI MS m/z 395[M+H]⁺.

EXAMPLE 2532-(4-((2-(4-Methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-(4-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.017 g, 0.043 mmol) was reacted with ammonia in methanol (7.0 M, 5mL), followed by formation of the hydrochloride salt to afford the titlecompound (0.012 g, 66%) as an orange-brown solid. MW=438.39. ¹H NMR(DMSO-d₆, 500 MHz) δ 13.38 (s, 1H), 11.19 (s, 1H), 9.32 (s, 1H), 7.53(s, 1H), 7.35 (d, J=8.0 Hz, 2H), 7.30 (d, J=8.0 Hz, 2H), 6.91 (s, 1H),6.09 (s, 1H), 4.03 (d, J=12.5 Hz, 2H), 3.48 (d, J=12.5 Hz, 2H),3.43-3.13 (m, 4H), 3.16-2.98 (m, 4H), 2.81-2.74 (m, 5H), 2.20-2.10 (m,2H); APCI MS m/z 366 [M+H]⁺.

EXAMPLE 2542-(4-((2-Morpholino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(4-((2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1, ethyl2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.120 g, 0.36 mmol) was reacted with morpholine (0.063 g, 0.73 mmol) toafford the title compound (0.034 g, 15%) as an orange foam. MW=381.47.APCI MS m/z 382 [M+H]⁺.

EXAMPLE 2542-(4-((2-Morpholino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-morpholino-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.034 g, 0.089 mmol) was reacted with ammonia in methanol (7.0 M, 4mL), followed by formation of the hydrochloride salt to afford the titlecompound (0.025 g, 73%) as a white solid. MW=388.89. ¹H NMR (DMSO-d₆,500 MHz) δ 12.68 (s, 1H), 9.16 (s, 1H), 7.51 (s, 1H), 7.33 (d, J=8.5 Hz,2H), 7.27 (d, J=8.5 Hz, 2H), 6.90 (s, 1H), 6.04 (s, 1H), 3.74-3.66 (m,4H), 3.40 (s, 2H), 3.35-3.28 (m, 4H), 2.98 (t, J=7.5 Hz, 2H), 2.77 (t,J=7.5 Hz, 2H), 2.14 (quin, J=7.5 Hz, 2H); APCI MS m/z 353 [M+H]⁺.

EXAMPLE 255(R)-2-(4-((2-(3-Methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of (R)-tert-butyl4-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-methylpiperazine-1-carboxylate

Following general procedure B1, ethyl2-(4-((2-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.094 g, 0.28 mmol) was reacted with (R)-tert-butyl2-methylpiperazine-1-carboxylate (0.112 g, 0.56 mmol) to afford thetitle compound (0.038 g, 27%) as an orange foam. MW=494.63. ¹H NMR(CDCl₃, 500 MHz) δ 7.26 (d, J=8.3 Hz, 2H), 7.13 (d, J=8.3 Hz, 2H), 6.14(s, 1H), 5.58 (s, 1H), 4.27 (br s, 1H), 4.17 (q, J=7.0 Hz, 2H),4.04-3.97 (m, 1H), 3.91-3.84 (m, 1H), 3.79-3.73 (m, 1H), 3.60 (s, 2H),2.88 (t, J=7.5 Hz, 2H), 2.86-2.78 (m, 1H), 2.70 (t, J=7.5 Hz, 2H), 2.11(quin, J=7.5 Hz, 2H), 1.47 (s, 9H), 1.27 (t, J=7.0 Hz, 3H), 1.20 (d,J=6.6 Hz, 3H); APCI MS m/z 495 [M+H]⁺.

Step 2. Preparation of (R)-methyl2-(4-((2-(3-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

A solution of (R)-tert-butyl4-(4-((4-(2-ethoxy-2-oxoethyl)phenyl)amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-2-yl)-2-methylpiperazine-1-carboxylate(0.038 g, 0.077 mmol) in HCl in methanol (1.25 M, 2 mL) was heated to65° C. for 2 h. The mixture was cooled and concentrated to afford crudeproduct. MW=380.45. APCI MS m/z 381 [M+H]⁺.

EXAMPLE 255.(R)-2-(4-((2-(3-Methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, (R)-methyl2-(4-((2-(3-methylpiperazin-1-yl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.077 mmol) was reacted with ammonia in methanol (7.0 M, 4 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.006 g, 18% over two steps) as a yellow solid. MW=438.39. ¹HNMR (DMSO-d₆, 500 MHz) δ 13.14 (s, 1H), 9.56-9.15 (m, 3H), 7.51 (s, 1H),7.34 (d, J=8.0 Hz, 2H), 7.28 (d, J=8.0 Hz, 2H), 6.91 (s, 1H), 6.10 (s,1H), 4.03 (d, J=13.5 Hz, 2H), 3.84 (d, J=13.5 Hz, 2H), 3.43-3.21 (m,5H), 3.15-2.96 (m, 4H), 2.77 (t, J=7.5 Hz, 2H), 2.20-2.10 (m, 2H), 1.26(d, J=6.5 Hz, 3H); APCI MS m/z 366 [M+H]⁺.

EXAMPLE 2562-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine1-oxide

To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine(0.165 g, 0.87 mmol) in methylene chloride (10 mL) was added MCBPA (77%,0.236 g, 1.0 mmol). The reaction stirred at rt for 16 h. After thistime, the mixture was diluted with methylene chloride and washedsequentially with water, a saturated solution of Na₂S₂O₃, a saturatedsolution of NaHCO₃, and brine. The organic layers were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate) to afford the title compound (0.106 g, 60%) as a white solid.MW=204.05. ¹H NMR (CDCl₃, 300 MHz) δ 7.34 (s, 1H), 3.27 (t, J=7.5 Hz,2H), 3.06 (t, J=7.5 Hz, 2H), 2.25 (quin, J=7.5 Hz, 2H); APCI MS m/z 204[M+H]⁺.

Step 2. Preparation of4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide

To a solution of cyclopentanol (0.050 g, 0.59 mmol) in NMP (3 mL) at rtwas added potassium tert-butoxide (0.060 g, 0.54 mmol). The mixture wasstirred at rt for 1 h. 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine1-oxide (0.100 g, 0.49 mmol) in NMP (1 mL) was added and the mixture washeated to 80° C. for 1 h. The mixture was diluted with methylenechloride and washed with water. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford crude product (0.140 g) as a brownoil. MW=253.72. ¹H NMR (CDCl₃, 300 MHz) δ 6.69 (s, 1H), 5.04 (s, 1H),3.23 (t, J=7.6 Hz, 2H), 2.99 (t, J=7.6 Hz, 2H), 2.20 (quin, J=7.6 Hz,2H), 2.00-1.56 (m, 8H); APCI MS m/z 254 [M+H]⁺.

Step 3. Preparation of4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine

To a solution of crude4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide(0.49 mmol) in methylene chloride (5 mL) was added phosphoroustrichloride (0.100 g, 0.74 mmol). The mixture stirred at rt for 2 h.After this time, the mixture was quenched with a saturated solution ofNaHCO₃ and extracted with methylene chloride. The organic layer wasdried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate) to afford the title compound (0.029 g, 25% overtwo steps) as a clear oil. MW=237.73. ¹H NMR (CDCl₃, 300 MHz) δ 6.45 (s,1H), 5.34-5.26 (m, 1H), 3.01-2.84 (m, 4H), 2.11 (quin, J=7.5 Hz, 2H),2.00-1.57 (m, 8H); APCI MS m/z 238 [M+H]⁺.

Step 4. Preparation of ethyl2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B2,4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.070g, 0.29 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.080 g,0.44 mmol) to afford the title compound (0.088 g, 78%) as a yellow foam.MW=380.48. APCI MS m/z 381 [M+H]⁺.

EXAMPLE 2562-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following genera procedure C, ethyl2-(4-((2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.088 g, 0.23 mmol) was reacted with ammonia in methanol (7.0 M, 3 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.029 g, 32%) as a white solid. MW=387.90. ¹H NMR (DMSO-d₆,500 MHz) δ 13.83 (s, 1H), 9.57 (s, 1H), 7.53 (s, 1H), 7.37 (d, J=8.0 Hz,2H), 7.29 (d, J=8.0 Hz, 2H), 6.91 (s, 1H), 6.14 (s, 1H), 4.98-4.93 (m,1H), 3.42 (s, 2H), 2.94 (t, J=7.5 Hz, 2H), 2.79 (t, J=7.5 Hz, 2H), 2.15(quin, J=7.5 Hz, 2H), 1.89-1.58 (m, 8H); APCI MS m/z 352 [M+H]⁺.

EXAMPLE 2572-(4-((2-(Cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure B1,4-chloro-2-(cyclopentyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.045g, 0.19 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.039 g, 0.28mmol), followed by formation of the hydrochloride salt to afford thetitle compound (0.050 g, 70%) as a white solid. MW=374.90. ¹H NMR(DMSO-d₆, 300 MHz) δ 13.82 (s, 1H), 9.52 (s, 1H), 7.33 (d, J=8.5 Hz,2H), 7.25 (d, J=8.5 Hz, 2H), 6.11 (s, 1H), 5.00-4.89 (m, 1H), 3.63 (t,J=7.0 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.84-2.69 (m, 4H), 2.15 (quin,J=7.5 Hz, 2H), 1.91-1.52 (m, 8H); APCI MS m/z 339 [M+H]⁺.

EXAMPLE 2582-(4-((2-(Cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine1-oxide

To a solution of cyclopentyl mercaptan (0.112 g, 1.10 mmol) in dioxane(4 mL) at rt was added potassium tert-butoxide (0.100 g, 0.88 mmol). Themixture was stirred at rt for 1 h. After this time,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.150 g, 0.74mmol) in dioxane (1 mL) was added and the mixture was heated to 100° C.for 1 h. Then, the mixture was diluted with methylene chloride andwashed with water. The organic layer were dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated. The residue waspurified by column chromatography (silica, dichloromethane/methanol) toafford the title compound (0.170 g, 86%) as a brown oil. MW=269.79. ¹HNMR (CDCl₃, 500 MHz) δ 6.99 (s, 1H) 3.60-3.52 (m, 1H), 3.22 (t, J=7.5Hz, 2H), 3.01 (t, J=7.5 Hz, 2H), 2.26-2.15 (m, 4H), 1.88-1.79 (m, 2H),1.77-1.64 (m, 4H); APCI MS m/z 270 [M+H]⁺.

Step 2. Preparation of4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta [b]pyridine

To a solution of4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine1-oxide (0.160 g, 0.59 mmol) in methylene chloride (10 mL) was addedphosphorous trichloride (0.1 mL, 0.89 mmol). The mixture stirred at rtfor 2 h. After this time, the mixture was quenched with a saturatedsolution of NaHCO₃ and extracted with methylene chloride. The organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the titlecompound (0.137 g, 91%) as a clear oil. MW=253.79. ¹H NMR (CDCl₃, 500MHz) δ 6.96 (s, 1H) 3.98-3.90 (m, 1H), 3.02 (t, J=7.5 Hz, 2H), 2.93 (t,J=7.5 Hz, 2H), 2.22-2.08 (m, 4H), 1.83-1.72 (m, 2H), 1.68-1.58 (4H);APCI MS m/z 254 [M+H]⁺.

Step 3. Preparation of ethyl2-(4-((2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.130g, 0.51 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.137 g,0.77 mmol) to afford crude product (0.220 g) as a colorless gum.MW=396.55. ¹H NMR (CDCl₃, 300 MHz) δ 7.27 (d, J=8.5 Hz, 2H), 7.12 (d,J=8.5 Hz, 2H), 6.74 (s, 1H), 5.62 (s, 1H), 4.17 (q, J=7.0 Hz, 2H),3.93-3.79 (m, 1H), 3.60 (s, 2H), 3.52-3.46 (m, 2H), 2.97 (t, J=7.5 Hz,2H), 2.74 (t, J=7.5 Hz, 2H), 2.22-2.02 (m, 4H), 1.83-1.51 (m, 6H), 1.27(t, J=7.0 Hz, 3H); APCI MS m/z 397 [M+H]⁺.

EXAMPLE 2582-(4-((2-(Cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

Following general procedure C, ethyl2-(4-((2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.51 mmol) was reacted with ammonia in methanol (7.0 M, 5 mL) to affordthe title compound (0.130 g, 69% over two steps) as an off-white solid.MW=367.51. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.00 (s, 1H), 7.44 (s, 1H), 7.23(d, J=8.5 Hz, 2H), 7.10 (d, J=8.5 Hz, 2H), 6.87 (s, 1H), 6.52 (s, 1H),3.82 (quin, J=7.0 Hz, 1H), 3.33 (s, 2H), 2.84-2.67 (m, 4H), 2.12-1.95(m, 4H), 1.73-1.39 (m, 6H); APCI MS m/z 368 [M+H]⁺.

EXAMPLE 2592-(4-((2-(Cyclopentylsulfonyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide

To a solution of2-(4-((2-(cyclopentylthio)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamide(0.095 g, 0.26 mmol) in methylene chloride (5 mL) at rt was added MCPBA(77%, 0.127 g, 0.52 mmol). The mixture stirred at rt for 1 h. After thistime, the mixture was diluted with methylene chloride and washedsequentially with water, a saturated solution of Na₂S₂O₃, a saturatedsolution of NaHCO₃, and brine. The organic layers were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.083 g, 81%) asa white solid. MW=399.51. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.53 (s, 1H), 7.47(s, 1H), 7.30 (d, J=8.5 Hz, 2H), 7.26 (s, 1H), 7.16 (d, J=8.5 Hz, 2H),6.87 (s, 1H), 3.99-3.89 (m, 1H), 3.38 (s, 2H), 2.90 (t, J=7.5 Hz, 2H),2.85 (t, J=7.5 Hz, 2H), 2.11 (quin, J=7.5 Hz, 2H), 1.87-1.74 (m, 4H),1.65-1.49 (m, 4H); APCI MS m/z 400 [M+H]⁺.

EXAMPLE 2602-(4-((2-Isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Step 1. Preparation of4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide

To a solution of iso-propanol (0.047 g, 0.79 mmol) in dioxane (3 mL) atrt was added potassium tert-butoxide (0.053 g, 0.47 mmol). The mixturewas stirred at rt for 30 min. Then,2,4-dichloro-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide (0.100 g, 0.39mmol) in dioxane (1 mL) was added and the mixture was heated undermicrowave irradiation to 100° C. for 30 min. After this time, themixture was diluted with methylene chloride and washed with water. Theorganic layer were dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated. The residue was purified by columnchromatography (silica, dichloromethane/methanol) to afford the titlecompound (0.079 g, 88%) as a white solid. MW=227.69. ¹H NMR (CDCl₃, 300MHz) δ 6.73 (s, 1H), 4.90-4.85 (m, 1H), 3.23 (t, J=7.5 Hz, 2H), 3.00 (t,J=7.5 Hz, 2H), 2.20 (quin, J=7.5 Hz, 2H), 1.44 (d, J=6.0 Hz, 6H); APCIMS m/z 228 [M+H]⁺.

Step 2. Preparation of4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine

To a solution of4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine 1-oxide(0.079 g, 0.35 mmol) in methylene chloride (5 mL) was added phosphoroustrichloride (0.096 g, 0.70 mmol). The mixture stirred at rt for 30 min.After this time, the mixture was quenched with a saturated solution ofNaHCO₃ and extracted with methylene chloride. The organic layer weredried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,hexanes/ethyl acetate) to afford the title compound (0.057 g, 77%) as aclear oil. MW=211.69. ¹H NMR (CDCl₃, 300 MHz) δ 6.47 (s, 1H), 5.27-5.18(m, 1H), 3.01-2.84 (m, 4H), 2.11 (quin, J=7.5 Hz, 2H), 1.31 (d, J=6.0Hz, 6H); APCI MS m/z 212 [M+H]⁺.

EXAMPLE 2602-(4-((2-Isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)ethanolhydrochloride

Following general procedure B1,4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (0.057 g,0.27 mmol) was reacted with 2-(4-aminophenyl)ethanol (0.056 g, 0.40mmol), followed by formation of the hydrochloride salt to afford thetitle compound (0.033 g, 35%) as a white solid. MW=348.87. ¹H NMR(DMSO-d₆, 300 MHz) δ 13.84 (s, 1H), 9.50 (s, 1H), 7.33 (d, J=8.5 Hz,2H), 7.25 (d, J=8.5 Hz, 2H), 6.12 (s, 1H), 4.82-4.67 (m, 1H), 3.64 (t,J=7.0 Hz, 2H), 2.93 (t, J=7.5 Hz, 2H), 2.83-2.69 (m, 4H), 2.15 (quin,J=7.5 Hz, 2H), 1.28 (d, J=6.0 Hz, 6H); APCI MS m/z 313 [M+H]⁺.

EXAMPLE 2612-(4-((2-Isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Step 1. Preparation of ethyl2-(4-((2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate

Following general procedure B1,4-chloro-2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridine (0.090 g,0.43 mmol) was reacted with ethyl 2-(4-aminophenyl)acetate (0.114 g,0.64 mmol) to afford the title compound (0.130 g, 86%) as a yellow gel.MW=354.44. APCI MS m/z 355 [M+H]⁺.

EXAMPLE 2612-(4-((2-Isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-isopropoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetate(0.130 g, 0.37 mmol) was reacted with ammonia in methanol (7.0 M, 4 mL),followed by formation of the hydrochloride salt to afford the titlecompound (0.112 g, 84%) as a white solid. MW=361.87. ¹H NMR (DMSO-d₆,500 MHz) δ 13.89 (s, 1H), 9.60 (s, 1H), 7.55 (s, 1H), 7.37 (d, J=8.0 Hz,2H), 7.29 (d, J=8.0 Hz, 2H), 6.91 (s, 1H), 6.16 (s, 1H), 4.75 (quin,J=6.0 Hz, 1H), 3.42 (s, 2H), 2.95 (t, J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz,2H), 2.16 (quin, J=7.5 Hz, 2H), 1.29 (d, J=6.0 Hz, 6H); APCI MS m/z 326[M+H]⁺.

EXAMPLE 2622-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetamidehydrochloride

Step 1. Preparation of2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbonitrile

To a suspension of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.250 g, 0.83 mmol) in dioxane (5 mL) was addedtetrakis(triphenylphosphine)palladium (0.096 g, 0.083 mmol) and zinccyanide (0.292 g, 2.5 mmol). The suspension was purged with nitrogen gasand then heated with microwave irradiation to 160° C. for h. After thistime, the mixture was diluted with a saturated solution of NaHCO₃ andextracted with ethyl acetate. The organic layer were dried overanhydrous sodium sulfate, filtered, and the filtrate was concentrated.The residue was purified by column chromatography (silica, hexanes/ethylacetate) to afford the title compound (0.157 g, 74%) as a white solid.MW=254.7. ¹H NMR (CDCl₃, 300 MHz) δ 8.01-7.96 (m, 1H), 7.85-7.77 (m,1H), 7.64 (s, 1H), 7.44-7.38 (m, 2H), 3.21-3.14 (m, 4H), 2.27 (quin,J=7.5 Hz, 2H); APCI MS m/z 255 [M+H]⁺.

Step 2. Preparation of2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde

To a solution of2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbonitrile(0.275 g, 1.08 mmol) in methylene chloride (15 mL) was added DIBAL (1.0M, 2.2 mL, 2.2 mmol) at −78° C. The solution was stirred at 0° C. for 4h. The reaction was quenched with methanol and HCl. The mixture wasdiluted with a saturated solution of NaHCO₃ and extracted with ethylacetate. The organic layer were dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.150 g, 48%) as a colorless oil. MW=257.71. ¹H NMR(CDCl₃, 500 MHz) δ 10.27 (s, 1H), 7.83 (s, 1H), 8.06-8.03 (m, 1H),7.91-7.87 (m, 1H), 7.45-7.37 (m, 2H), 3.33 (t, J=7.5 Hz, 2H), 3.15 (t,J=7.5 Hz, 2H), 2.27 (quin, J=7.5 Hz, 2H); APCI MS m/z 258 [M+H]⁺.

Step 3. Preparation of ethyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetate

To a suspension of2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine-4-carbaldehyde(0.210 g, 0.81 mmol) in dioxane (10 mL) was added palladium chloride(0.007 g, 0.040 mmol), trinaphthyl phosphine (0.017 g, 0.040 mmol),potassium carbonate 0. (336 g, 2.43 mmol), and methyl2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetate (0.200g, 0.97 mmol). The mixture was purged with nitrogen and then heated to100° C. under sealed conditions for 16 h. After this time, the mixturewas diluted with water and extracted with ethyl acetate. The organiclayer were dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the titlecompound (0.250 g, 75%) as a white foam. MW=421.9. ¹H NMR (CDCl₃, 500MHz) δ 8.01-7.97 (m, 1H), 7.87-7.83 (m, 1H), 7.76 (s, 1H), 7.40-7.23 (m,6H), 5.81 (s, 1H), 4.13 (q, J=7.0 Hz, 2H), 3.59 (s, 2H), 3.07-2.98 (m,2H), 2.87-2.79 (m, 1H), 2.64-2.49 (m, 1H), 2.08 (quin, J=7.5 Hz, 2H),1.30-1.21 (m, 3H); APCI MS m/z 422 [M+H]⁺.

EXAMPLE 2622-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetamidehydrochloride

Following general procedure C, ethyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetate(0.018 g, 0.043 mmol) was reacted with ammonia in methanol (7.0 M, 4mL), followed by formation of the hydrochloride salt to afford the titlecompound (0.010 g, 55%) as a white solid. MW=429.34. ¹H NMR (DMSO-d₆,500 MHz) δ 8.11-8.09 (m, 1H), 8.06 (s, 1H), 8.01-7.97 (m, 1H), 7.60-7.54(m, 2H), 7.43 (s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.21 (d, J=8.0 Hz, 2H),6.82 (s, 1H), 5.80 (s, 1H), 3.33 (s, 2H), 3.06-2.93 (m, 3H), 2.71-2.61(m, 2H), 2.11-2.01 (m, 2H); APCI MS m/z 393 [M+H]⁺.

EXAMPLE 2632-(4-((2-(3-Chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)ethanol

Following general procedure E1, ethyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)(hydroxy)methyl)phenyl)acetate(0.065 g, 0.15 mmol) was reacted with DIBAL (1.0 M, 0.46 mL, 0.46 mmol),followed by formation of the hydrochloride salt to afford the titlecompound (0.047 g, 73%) as a white solid. MW=379.88. ¹H NMR (DMSO-d₆,500 MHz) δ 8.10-8.07 (m, 1H), 8.03 (s, 1H), 8.00-7.97 (m, 1H), 7.59-7.52(m, 2H), 7.31 (d, J=8.0 Hz, 2H), 7.16 (d, J=8.0 Hz, 2H), 5.78 (s, 1H),3.56 (t, J=7.0 Hz, 2H), 3.03-2.90 (m, 3H), 2.71-2.60 (m, 3H), 2.09-2.00(m, 2H); APCI MS m/z 380 [M+H]⁺.

EXAMPLE 2642-(4-((6-(3-Chlorophenyl)-2-ethylpyrimidin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of 6-(3-chlorophenyl)-2-ethylpyrimidin-4(3H)-one

To a solution of ammonium hydroxide (3 mL) and ammonia in methanol (7.0N, 10 mL) in ethanol (6 mL) was added 1,1,1-triethoxypropane (6.2 g,35.3 mmol) and ethyl 3-(3-chlorophenyl)-3-oxopropanoate (4.0 g, 17.6mmol) dropwise as a solution in ethanol (10 mL). Once the addition wascomplete, ammonium hydroxide (10 mL) was added. The mixture was heatedwith stirring in a sealed flask at 60° C. overnight. After this time,the mixture was cooled to rt and concentrated. The residue was purifiedby column chromatography (silica, hexanes/DCM) to afford the titlecompound (0.250 g, 6%) as a white solid. MW=234.68. ¹H NMR (CDCl₃, 500MHz) δ 8.03 (t, J=1.9 Hz, 1H), 7.86-7.82 (m, 1H), 7.46-7.38 (m, 2H),6.73 (s, 1H), 2.80 (q, J=7.6 Hz, 2H), 1.42 (t, J=7.6 Hz, 3H); APCI MSm/z 235 [M+H]⁺.

Step 2. Preparation of 4-chloro-6-(3-chlorophenyl)-2-ethylpyrimidine

A mixture of 6-(3-chlorophenyl)-2-ethylpyrimidin-4(3H)-one (0.240 g, 1.0mmol) and POCl₃ (5 mL) was heated to 85° C. for 6 h. After this time,the reaction was cooled, neutralized with saturated aqueous sodiumbicarbonate, and extracted with methylene chloride. The combined organiclayer was dried over anhydrous sodium sulfate, filtered, and thefiltrate was concentrated. The residue was purified by columnchromatography (silica, hexanes/ethyl acetate) to afford the titlecompound as an off-white solid (0.210 g, 81%). MW=253.13. ¹H NMR (CDCl₃,500 MHz) δ 8.10 (t, J=1.9 Hz, 1H), 7.96-7.92 (m, 1H), 7.55-7.41 (m, 3H),3.03 (q, J=7.6 Hz, 2H), 1.55 (s, 1H), 1.42 (t, J=7.6 Hz, 3H); APCI MSm/z 254 [M+H]⁺.

EXAMPLE 2642-(4-((6-(3-Chlorophenyl)-2-ethylpyrimidin-4-yl)amino)phenyl)ethanol

A solution of 4-chloro-6-(3-chlorophenyl)-2-ethylpyrimidine (0.100 g,0.39 mmol), 4-aminophenethyl alcohol (0.081 g, 0.59 mmol) and HCl indioxane (4.0 M, 0.023 mL, 0.59 mmol) in ethanol (2 mL) was heated to 85°C. for 3 h. After this time, the reaction was cooled, neutralized withsaturated aqueous sodium bicarbonate, and extracted with ethyl acetate.The combined organic layers were dried over anhydrous sodium sulfate,filtered and the filtrate was concentrated. The residue was purified bypreparative HPLC (water/acetonitrile with 0.05% TFA) to afford the titlecompound (0.027 g, 27%) as a light yellow solid. MW=353.85. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.01 (t, J=1.8 Hz, 1H), 7.88 (d, J=7.6 Hz, 1H),7.69-7.57 (m, 4H), 7.25 (d, J=8.3 Hz, 2H), 7.04 (s, 1H), 3.61 (t, J=7.0Hz, 2H), 2.87 (q, J=7.6 Hz, 2H), 2.72 (t, J=7.0 Hz, 2H), 1.33 (t, J=7.6Hz, 3H); APCI MS m/z 354 [M+H]⁺.

EXAMPLE 2652-(4-((6-(3-chlorophenyl)-2-ethylpyrimidin-4-yl)amino)phenyl)acetamide

A mixture of 4-chloro-6-(3-chlorophenyl)-2-ethylpyrimidine (0.080 g,0.32 mmol) and 2-(4-aminophenyl)acetamide (0.057 g, 0.38 mmol) and 4MHCl in dioxane (2 drops) in acetic acid (2.5 mL) was heated for 2.5 h at85° C. After this time, the mixture was cooled to 0° C., neutralizedwith NaHCO₃, extracted with CH₂C2 (2×30 mL) and EtOAc, dried (Na₂SO₄),filtered, and concentrated. The residue was purified by silica gelchromatography eluting with methylene chloride and methanol to affordthe title compound (0.045 g, 40%) as a white solid. MW=366.84. ¹H NMR(DMSO-d₆, 500 MHz) δ 9.60 (s, 1H), 8.05 (d, J=2.0 Hz, 1H), 7.95-7.93 (m,1H), 7.64 (d, J=8.4 Hz, 2H), 7.58-7.54 (m, 2H), 7.42 (br s, 1H), 7.23(d, J=8.4 Hz, 2H), 7.05 (s, 1H), 6.85 (br s, 1H), 2.81 (q, J=7.6 Hz,2H), 1.32 (t, J=7.6 Hz, 3H); ESI MS m/z 367 [M+H]⁺.

EXAMPLE 2663-(3-(2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)phenyl)propan-1-olhydrochloride

A mixture of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.070 g, 0.23 mmol), (3-(3-hydroxypropyl)phenyl)boronicacid (0.054 g, 0.30 mmol), 2M Na₂CO₃ (0.5 m), and Pd(PPh₃)₄ (0.013 g,0.012 mmol) in dioxane (50 mL) was heated at reflux under nitrogen for2.5 h. After this time, the mixture was diluted with ethyl acetate (100mL), washed with water (100 mL), dried (Na₂SO₄), filtered, andconcentrated. The resulting residue was purified by silica gelchromatography eluting with 20% ethyl acetate/hexanes to 100% ethylacetate to afford the free base of title compound (0.028 g, 34%) as awhite foam. This material was redissolved in Et₂O (20 mL) and 4N HCl indioxane (0.1 mL) added. The mixture was concentrated, triturated withEt₂O, and lyophilized with a water/acetonitrile/methanol mixture toafford the title compound as a white solid. MW=363.88. ¹H NMR (DMSO-d₆,300 MHz) δ 8.21 (s, 1H), 8.12-8.08 (m, 1H), 7.92 (s, 1H), 7.58-7.33 (m,6H), 3.45 (t, J=6.4 Hz, 2H), 3.16-3.01 (m, 4H), 2.74-2.69 (m, 2H),2.19-2.08 (m, 2H), 1.83-0.83 (m, 2H); APCI MS m/z 364 [M+H]⁺.

EXAMPLE 2672-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)sulfonyl)phenyl)acetamide

Step 1. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)thio)phenyl)acetate

A mixture of4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.120 g, 0.40 mmol), methyl 2-(4-mercaptophenyl)acetate(0.100 g, 0.55 mmol), and Et₃N (0.145 g, 1.3 mmol) in DMF was heated at110° C. for 24 h. After this time, the mixture was concentrated, dilutedwith EtOAc (100 mL), washed with 10% aqueous LiCl (2×100 mL), dried(Na₂SO₄), filtered, and concentrated. The residue was purified by silicagel chromatography eluting with 100% hexanes to 1:1 ethylacetate/hexanes to afford the title compound (0.164 g, 100%) as a whitesolid. MW=409.93. ¹H NMR (CDCl₃, 300 MHz) δ 7.78-7.77 (m, 1H), 7.61-7.46(m, 3H), 7.37 (d, J=8.2 Hz, 2H), 7.30-7.28 (m, 3H), 6.89 (s, 1H), 3.73(s, 3H), 3.70 (s, 2H), 3.09 (t, J=7.7 Hz, 2H), 2.90 (t, J=7.4 Hz, 2H),2.24-2.05 (m, 4H); APCI MS m/z 410 [M+H]⁺.

Step 2. Preparation of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)sulfonyl)phenyl)acetate

A solution of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)thio)phenyl)acetate(0.164 g, 0.40 mmol) and m-CPBA (0.269 g, 1.2 mmol) in CH₂C2 (15 mL) wasstirred at room temperature for 2 h. After this time, the mixture wasdiluted with CH₂Cl₂(100 mL), washed with water (100 mL) and saturatedNaHCO₃(100 mL), dried (MgSO4), filtered, and concentrated. The residuewas purified by silica gel chromatography eluting with 100% hexanes to1:1 ethyl acetate/hexanes to afford the title compound (0.109 g, 62%) asa white solid. MW=441.93. ¹H NMR (CDCl₃, 300 MHz) δ 8.09-8.0 (m, 2H),7.97-7.85 (m, 3H), 7.57-7.39 (m, 4H), 3.75-3.68 (m, 5H), 3.18-3.07 (m,4H), 2.22-2.05 (m, 2H); APCI MS m/z 442 [M+H]⁺.

EXAMPLE 2672-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)sulfonyl)phenyl)acetamide

A suspension of methyl2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)sulfonyl)phenyl)acetate(0.109 g, 0.25 mmol) in 7N NH₃ in MeOH was heated at 100° C. in a sealedtube. After 24 h, the mixture was concentrated and purified by silicagel chromatography eluting with 100% methylene chloride to 1:1 methylenechloride/89:9:1 (methylene chloride/methanol/concentrated ammoniumhydroxide) to afford the title compound (0.055 g, 53%) as a white solid.MW=426.92. ¹H NMR (DMSO-d₆, 300 MHz) δ 8.20-8.18 (m, 2H), 8.10-8.08 (m,1H), 8.03 (d, J=8.4 Hz, 2H), 7.56-7.51 (m, 5H), 6.98 (s, 1H), 3.50 (s,2H), 3.12 (t, J=7.6 Hz, 2H), 3.03 (t, J=7.8 Hz, 2H), 2.13-2.08 (m, 2H);APCI MS m/z 427 [M+H]⁺.

EXAMPLE 2684-((4-(2-hydroxyethyl)phenyl)amino)-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Following general procedure G,5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.123 g, 0.30 mmol) was reacted with2-(4-aminophenyl)ethanol (0.045 g, 0.33 mmol) to afford the desiredproduct (0.081 g, 68%) as a light yellow solid. MW=395.47. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.72 (s, 1H), 8.29-8.25 (m, 2H), 7.61-7.49 (m, 5H),7.30 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.76-3.71 (m, 2H),3.67-3.61 (m, 2H), 3.07 (t, J=6.5 Hz, 2H), 2.75 (t, J=7.0 Hz, 2H),2.43-2.35 (m, 2H); APCI MS m/z 396 [M+H]⁺.

EXAMPLE 2692-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure G,5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.125 g, 0.31 mmol) was reacted with2-(4-aminophenyl)acetamide (0.051 g, 0.34 mmol) to afford the desiredproduct (0.077 g, 61%) as a white solid. MW=408.47. ¹H NMR (DMSO-d₆, 500MHz) δ 8.74 (s, 1H), 8.30-8.25 (m, 2H), 7.61 (d, J=8.5 Hz, 2H),7.59-7.50 (m, 3H), 7.48 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 6.89 (s, 1H),3.77-3.71 (m, 2H), 3.40 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m,2H); APCI MS m/z 409 [M+H]⁺.

EXAMPLE 2702-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-propylacetamide

Step 1. ethyl2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

Following general procedure G,5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (1.0 g, 2.46 mmol) was reacted with ethyl2-(4-aminophenyl)acetate (0.527 g, 2.94 mmol) to afford the desiredproduct (0.83 g, 77%) as a light yellow solid. MW=437.51. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.77 (s, 1H), 8.28-8.24 (m, 2H), 7.64-7.49 (m, 5H),7.34 (d, J=8.5 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.76-3.72 (m, 2H), 3.70(s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H), 1.20 (t, J=7.0 Hz,3H); APCI MS m/z 438 [M+H]⁺.

Step 2.2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)aceticacid

Following general procedure D, ethyl2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate(0.80 g, 1.83 mmol) was reacted with lithium hydroxide (0.380 g, 9.15mmol) to afford the desired product (0.650 g, 86%) as a light yellowsolid. MW=409.46. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.34 (s, 1H), 8.76 (s,1H), 8.29-8.25 (m, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.59-7.49 (m, 3H), 7.33(d, J=8.5 Hz, 2H), 3.76-3.72 (m, 2H), 3.60 (s, 2H), 3.08 (t, J=6.5 Hz,2H), 2.43-2.35 (m, 2H); APCI MS m/z 410 [M+H]⁺.

Step 3.2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-propylacetamide

To a solution of2-(4-((5,5-dioxido-2-phenyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)aceticacid (0.115 g, 0.28 mmol) in DMF (4 mL) was added EDC (0.107 g, 0.56mmol), HOBT (0.076 g, 0.56 mmol) and n-propylamine (0.12 mL, 1.4 mmol).The mixture was stirred at rt for 16 h. The mixture was diluted withethyl acetate and then washed with water. The organic layer were driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the desired product (0.110 g, 87%)as a white solid. MW=450.55. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.74 (s, 1H),8.29-8.25 (m, 2H), 8.05-7.99 (m, 1H), 7.63-7.49 (m, 5H), 7.33 (d, J=8.5Hz, 2H), 3.76-3.71 (m, 2H), 3.42 (s, 2H), 3.10-2.99 (m, 4H), 2.42-2.35(m, 2H), 1.45-1.38 (m, 2H), 0.85 (t, J=7.5 Hz, 3H); APCI MS m/z 451[M+H]⁺.

EXAMPLE 2712-(4-((2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Step 1. Preparation of2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol

To a solution of 3-chlorobenzimidamide (4.3 g, 27.7 mmol) in ethanol(120 mL) was added methyl 3-oxotetrahydro-2H-thiopyran-2-carboxylate(4.82 g, 27.7 mmol) and sodium methoxide (1.8 g, 33.2 mmol). The mixturewas stirred at 85° C. for 16 h. After this time, the mixture wasconcentrated after which ethanol (10 mL) was added and the suspensionwas chilled to 0° C. HCl (2 M, 50 mL) was added and the suspension wasfiltered and washed with water. The solid was dried under heat andvacuum to afford the title compound (5.2 g, 67%) as a light yellowsolid. MW=278.75. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.81 (s, 1H), 8.12 (s,1H), 8.03 (d, J=7.5 Hz, 1H), 7.63-7.58 (m, 1H), 7.56-7.51 (m, 1H),3.01-2.95 (m, 2H), 2.74 (t, J=6.0 Hz, 2H), 2.12-2.04 (m, 2H); APCI MSm/z 279 [M+H]⁺.

Step 2. Preparation of2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate

To a suspension of2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (5.2g, 18.6 mmol) in methylene chloride (200 mL) at 0° C. was addedN,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (5.2 mL, 37.3mmol) and trifluoromethanesulfonic acid (3.7 mL, 22.4 mmol). Thesuspension was warmed to rt and stirred for 3 h. The mixture was cooledto 0° C. and the reaction was quenched with a saturated solution ofNaHCO₃. The organic layer was washed a saturated solution of NaHCO₃ andbrine. The organic layers were dried over anhydrous sodium sulfate,filtered and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, methylene chloride) to afford titlecompound (6.6 g, 86%) as a white solid. MW=410.82. ¹H NMR (CDCl₃, 300MHz) δ 8.35-8.31 (m, 1H), 8.25-8.18 (m, 1H), 7.48-7.36 (m, 2H),3.18-3.05 (m, 4H), 2.38-2.27 (m, 2H); APCI MS m/z 411 [M+H]⁺.

EXAMPLE 2712-(4-((2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure H,2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.125 g, 0.30 mmol) was reacted with2-(4-aminophenyl)acetamide (0.050 g, 0.33 mmol) to afford the titlecompound (0.101 g, 82%) as a white solid. MW=410.92. ¹H NMR (DMSO-d₆,500 MHz) δ 8.25-8.21 (m, 1H), 8.19 (s, 1H), 8.17-8.13 (m, 1H), 7.61 (d,J=8.5 Hz, 2H), 7.52-7.41 (m, 3H), 7.25 (d, J=8.5 Hz, 2H), 3.37 (s, 2H),3.22-3.16 (m, 2H), 2.90 (t, J=6.5 Hz, 2H), 2.22-2.16 (m, 2H); APCI MSm/z 411 [M+H]⁺.

EXAMPLE 2722-(4-((2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)ethanol

Following general procedure H,2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.120 g, 0.29 mmol) was reacted with2-(4-aminophenyl)ethanol (0.044 g, 0.32 mmol) to afford the titlecompound (0.101 g, 87%) as a white solid. MW=397.92. ¹H NMR (DMSO-d₆,500 MHz) δ 8.20-8.17 (m, 2H), 8.16-8.12 (m, 1H), 7.58 (d, J=8.5 Hz, 2H),7.51-7.46 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.5 Hz, 1H),3.65-3.59 (m, 2H), 3.20-3.16 (m, 2H), 2.90 (t, J=6.0 Hz, 2H), 2.73 (t,J=7.0 Hz, 2H), 2.22-2.15 (m, 2H); APCI MS m/z 398 [M+H]⁺.

EXAMPLE 2732-(3-Chlorophenyl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Step 1. Preparation of2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate

To a solution of2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (4.2 g, 10.2 mmol) in methylene chloride (150mL) was added MCBPA (77%, 6.87 g, 30.7 mmol). The reaction stirred at rtfor 4 h. The mixture was diluted with methylene chloride and washed withwater, a saturated solution of Na₂S₂O₃, a saturated solution of NaHCO₃,and brine. The organic layers were dried over anhydrous sodium sulfate,filtered and the filtrate was concentrated to afford the title compound(4.48 g, 98%) as a white solid. MW=442.82. ¹H NMR (CDCl₃, 500 MHz) δ8.41-8.39 (m, 1H), 8.32-8.28 (m, 1H), 7.59-7.54 (m, 1H), 7.49-7.44 (m,1H), 3.53-3.47 (m, 2H), 3.26 (t, J=6.0 Hz, 2H), 2.62-2.54 (m, 2H); APCIMS m/z 443 [M+H]⁺.

EXAMPLE 2732-(3-Chlorophenyl)-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Following general procedure H,2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.124 g, 0.28 mmol) was reacted with2-(4-aminophenyl)ethanol (0.042 g, 0.31 mmol) to afford the titlecompound (0.105 g, 87%) as a white solid. MW=429.92. ¹H NMR (DMSO-d₆,500 MHz) δ 8.77 (s, 1H), 8.22-8.17 (m, 2H), 7.65-7.61 (m, 1H), 7.58-7.52(m, 3H), 7.29 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.77-3.71 (m,2H), 3.67-3.61 (m, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.76 (t, J=7.0 Hz, 2H),2.43-2.35 (m, 2H); APCI MS m/z 430 [M+H]⁺.

EXAMPLE 2742-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure H,2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.127 g, 0.29 mmol) was reacted with2-(4-aminophenyl)acetamide (0.047 g, 0.32 mmol) to afford the titlecompound (0.074 g, 61%) as a light yellow solid. MW=442.92. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.79 (s, 1H), 8.24-8.17 (m, 2H), 7.65-7.54 (m, 4H),7.48 (s, 1H), 7.33 (d, J=8.5 Hz, 2H), 6.89 (s, 1H), 3.77-3.71 (m, 2H),3.41 (s, 2H), 3.08 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 443[M+H]⁺.

EXAMPLE 2752-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)aceticacid

Step 1. Preparation of ethyl2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate

Following general procedure H,2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (1.0 g, 2.26 mmol) was reacted with ethyl2-(4-aminophenyl)acetate (0.445 g, 2.49 mmol) to afford the titlecompound (0.827 g, 78%) as a light yellow solid. MW=471.96. APCI MS m/z472 [M+H]⁺.

EXAMPLE 2752-(4-((2-(3-Chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)aceticacid

Following general procedure D, ethyl2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetate (0.82 g, 1.74 mmol) wasreacted with lithium hydroxide (0.365 g, 8.7 mmol) to afford the desiredproduct (0.675 g, 87%) as a light yellow solid. MW=443.90. ¹H NMR(DMSO-d₆, 500 MHz) δ 12.33 (s, 1H), 8.81 (s, 1H), 8.23-8.16 (m, 2H),7.66-7.53 (m, 4H), 7.33 (d, J=8.5 Hz, 2H), 3.77-3.71 (m, 2H), 3.61 (s,2H), 3.09 (t, J=6.5 Hz, 2H), 2.43-2.35 (m, 2H); APCI MS m/z 444 [M+H]⁺.

EXAMPLE 2762-(4-((2-(3-Chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)-N-propylacetamide

To a solution of2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)aceticacid (0.125 g, 0.28 mmol) in DMF (5 mL) was added EDC (0.108 g, 0.56mmol), HOBT (0.076 g, 0.56 mmol) and n-propylamine (0.12 mL, 1.4 mmol).The mixture was stirred at rt for 2 d. After this time, the mixture wasdiluted with ethyl acetate and then washed with water. The organic layerwere dried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated. The residue was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (0.113 g, 83%) asalight yellow solid. MW=485.00. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.79 (s,1H), 8.22-8.16 (m, 2H), 8.06-8.00 (m, 1H), 7.65-7.61 (m, 1H), 7.59-7.53(m, 3H), 7.33 (d, J=8.5 Hz, 2H), 3.77-3.71 (m, 2H), 3.43 (s, 2H), 3.08(t, J=6.5 Hz, 2H), 3.05-2.99 (m, 2H), 2.43-2.35 (m, 2H), 1.45-1.38 (m,2H), 0.84 (t, J=7.5 Hz, 3H); APCI MS m/z 485 [M+H]⁺.

EXAMPLE 2772-(4-((2-(3-Chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetamide

Step 1. Preparation of methyl2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate

Following general procedure H,2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.250 g, 0.56 mmol) was reacted with methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.160 g, 0.56 mmol) to afford the title compound (0.058 g, 22%) as awhite solid. MW=456.9. ¹H NMR (CDCl₃, 500 MHz) δ 8.28 (t, J=1.2 Hz, 1H),8.30-8.26 (m, 1H), 7.52-7.45 (m, 3H), 7.42-7.37 (m, 1H), 7.23 (d, J=8.0Hz, 2H), 4.60 (s, 2H), 3.67 (s, 3H), 3.60 (s, 2H), 3.50-3.45 (m, 2H),3.18 (t, J=6.5 Hz, 2H), 2.54-2.48 (m, 2H); APCI MS m/z 457 [M+H]⁺.

Step 2. Preparation of2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)aceticacid

Following general procedure D, methyl2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate(0.058 g, 0.13 mmol) was reacted with lithium hydroxide (0.026 g, 0.64mmol) to afford the title compound (0.042 g, 75%) as a yellow-brownsolid. MW=442.92. ¹H NMR (DMSO-d₆, 300 MHz) δ 12.29 (s, 1H), 8.32-8.24(m, 2H), 7.71-7.53 (m, 2H), 7.38 (d, J=8.0 Hz, 2H), 7.20 (d, J=8.0 Hz,2H), 4.53 (s, 2H), 3.80-3.70 (m, 2H), 3.52 (s, 2H), 3.21 (t, J=6.0 Hz,2H), 2.42-2.31 (m, 2H); APCI MS m/z 443 [M+H]⁺.

EXAMPLE 2772-(4-((2-(3-Chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetamide

To a solution of2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)aceticacid (0.040 g, 0.090 mmol) in DMF (2 mL) was added EDC (0.034 g, 0.18mmol), HOBT (0.024 g, 0.18 mmol) and ammonia in methanol (0.13 mL, 0.90mmol). The mixture was sealed and stirred at 85° C. for 16 h. Themixture was diluted with ethyl acetate and then washed with water. Theorganic layer were dried over anhydrous sodium sulfate, filtered, andthe filtrate was concentrated. The residue was purified by columnchromatography (silica, dichloromethane/ethyl acetate) to afford thetitle compound (0.025 g, 62%) as a white solid. MW=441.93. ¹H NMR(DMSO-d₆, 500 MHz) δ 8.30-8.26 (m, 2H), 7.69-7.64 (m, 1H), 7.61-7.56 (m,1H), 7.40 (s, 1H), 7.37 (d, J=8.0 Hz, 2H), 7.19 (d, J=8.0 Hz, 2H), 6.82(s, 1H), 4.52 (s, 2H), 3.77-3.71 (m, 2H), 3.32 (s, 2H), 3.21 (t, J=6.5Hz, 2H), 2.40-2.38 (m, 2H); APCI MS m/z 442 [M+H]⁺.

EXAMPLE 2782-(3-chlorophenyl)-4-(4-(2-hydroxyethyl)benzyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Following general procedure E1, methyl2-(4-((2-(3-chlorophenyl)-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate(0.060 g, 0.13 mmol) was reacted with DIBAL (1.0 M, 0.65 mL, 0.65 mmol)to afford the title compound (0.045 g, 81%) as a white solid. MW=428.93.¹H NMR (DMSO-d₆, 500 MHz) δ 8.29-8.25 (m, 2H), 7.67-7.64 (m, 1H),7.61-7.56 (m, 1H), 7.34 (d, J=8.5 Hz, 2H), 7.15 (d, J=8.5 Hz, 2H), 4.58(t, J=5.5 Hz, 1H), 4.51 (s, 2H), 3.76-3.71 (m, 2H), 3.59-3.53 (m, 2H),2.68 (t, J=7.5 Hz, 2H), 2.40-2.32 (m, 2H); APCI MS m/z 429 [M+H]⁺.

EXAMPLE 2792-(4-((2-(3-Chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol

To a solution of 3-chlorobenzimidamide (4.8 g, 31.2 mmol) in ethanol(150 mL) was added methyl 3-oxotetrahydrothiophene-2-carboxylate (5.0 g,31.2 mmol) and sodium methoxide (1.7 g, 31.2 mmol). The mixture wasstirred at 85° C. for 16 h. The mixture was concentrated after whichethanol (10 mL) was added and the suspension was chilled to 0° C. HCl (2M, 50 mL) was added and the suspension was filtered and washed withwater. The solid was purified by column chromatography (silica,dichloromethane/methanol) to afford the title compound (1.9 g, 23%) as abrown solid. MW=264.73. ¹H NMR (DMSO-d₆, 500 MHz) δ 12.85 (s, 1H), 8.13(s, 1H), 8.07-8.01 (m, 1H), 7.63-7.59 (m, 1H), 7.56-7.51 (m, 1H),3.41-3.24 (m, 4H); APCI MS m/z 265 [M+H]⁺.

Step 2. Preparation of2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate

To a suspension of2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-ol (1.9 g, 7.2mmol) in methylene chloride (50 mL) at 0° C. was addedN,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (2.0 mL, 14.4mmol) and trifluoromethanesulfonic acid (1.3 mL, 7.9 mmol). Thesuspension was warmed to rt and stirred for 3 h. The mixture was cooledto 0° C. and the reaction was quenched with a saturated solution ofNaHCO₃. The organic layer was washed a saturated solution of NaHCO₃ andbrine. The organic layers were dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (1.23 g, 44%) as a light yellow solid. MW=396.79. ¹H NMR(CDCl₃, 500 MHz) δ 8.35-8.32 (m, 1H), 8.24-8.20 (m, 1H), 7.48-7.38 (m,2H), 3.59-3.49 (m, 4H); APCI MS m/z 397 [M+H]⁺.

EXAMPLE 2792-(4-((2-(3-Chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)ethanol

Following general procedure H,2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.094 g, 0.24 mmol) was reacted with2-(4-aminophenyl)ethanol (0.033 g, 0.24 mmol) to afford the titlecompound (0.062 g, 68%) as a white solid. MW=383.89. ¹H NMR (DMSO-d₆,500 MHz) δ 8.81 (s, 1H), 8.24-8.15 (m, 2H), 7.60 (d, J=8.5 Hz, 2H),7.53-7.48 (m, 2H), 7.21 (d, J=8.5 Hz, 2H), 4.63 (t, J=5.5 Hz, 1H),3.66-3.59 (m, 2H), 3.46-3.40 (m, 2H), 3.35-3.32 (m, 2H), 2.72 (t, J=7.0Hz, 2H); APCI MS m/z 384 [M+H]⁺.

EXAMPLE 2802-(4-((2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure H,2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.100 g, 0.25 mmol) was reacted with2-(4-aminophenyl)acetamide (0.038 g, 0.25 mmol) to afford the titlecompound (0.057 g, 57%) as a white solid. MW=396.89. ¹H NMR (DMSO-d₆,500 MHz) δ 8.85 (s, 1H), 8.25-8.17 (m, 2H), 7.63 (d, J=8.5 Hz, 2H),7.53-7.49 (m, 2H), 7.44 (s, 1H), 7.25 (d, J=8.5 Hz, 2H), 6.86 (s, 1H),3.47-3.40 (m, 2H), 3.38-3.32 (m, 4H); APCI MS m/z 397 [M+H]⁺.

EXAMPLE 2812-(3-Chlorophenyl)-4-((4-(2-hydroxyethyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine5,5-dioxide

Step 1. Preparation of2-(3-chlorophenyl)-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate

To a solution of2-(3-chlorophenyl)-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (1.0 g, 2.52 mmol) in methylene chloride (25mL) was added MCBPA (77%, 1.69 g, 7.56 mmol). The reaction stirred at rtfor 16 h. The mixture was diluted with methylene chloride and washedwith water, a saturated solution of Na₂S₂O₃, a saturated solution ofNaHCO₃, and brine. The organic layers were dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated to afford the titlecompound (1.0 g, 92%) as a white solid. MW=428.79. ¹H NMR (CDCl₃, 500MHz) δ 8.44 (s, 1H), 8.36-8.32 (m, 1H), 7.62-7.55 (m, 1H), 7.51-7.45 (m,1H), 3.75-3.61 (m, 4H); APCI MS m/z 429 [M+H]⁺.

EXAMPLE 2812-(3-Chlorophenyl)-4-((4-(2-hydroxyethyl)phenyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine5,5-dioxide

Following general procedure H,2-(3-chlorophenyl)-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.095 g, 0.22 mmol) was reacted with2-(4-aminophenyl)ethanol (0.036 g, 0.26 mmol) to afford the titlecompound (0.060 g, 65%) as a white solid. MW=415.89. ¹H NMR (DMSO-d₆,500 MHz) δ 9.51 (s, 1H), 8.24-8.17 (m, 2H), 7.64-7.60 (m, 1H), 7.58-7.53(m, 3H), 7.27 (d, J=8.5 Hz, 2H), 4.65 (t, J=5.5 Hz, 1H), 3.72 (t, J=7.0Hz, 2H), 3.67-3.62 (m, 2H), 3.44-3.38 (m, 2H), 2.76 (t, J=7.0 Hz, 2H);APCI MS m/z 416 [M+H]⁺.

EXAMPLE 2822-(4-((2-(3-chlorophenyl)-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure H,2-(3-chlorophenyl)-5,5-dioxido-6,7-dihydrothieno[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.100 g, 0.23 mmol) was reacted with2-(4-aminophenyl)acetamide (0.042 g, 0.28 mmol) to afford the titlecompound (0.070 g, 70%) as a white solid. MW=428.89. ¹H NMR (DMSO-d₆,500 MHz) δ 9.55 (s, 1H), 8.24-8.18 (m, 2H), 7.65-7.52 (m, 4H), 7.48 (s,1H), 7.30 (d, J=8.0 Hz, 2H), 6.89 (s, 1H), 3.72 (t, J=7.0 Hz, 2H),3.46-3.39 (m, 4H); APCI MS m/z 429 [M+H]⁺.

EXAMPLE 2832-(4-((2-Cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)ethanol

Step 1. Preparation of2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol

To a solution of cyclopentanecarboximidamide (3.2 g, 28.0 mmol) inethanol (150 mL) was added methyl3-oxotetrahydro-2H-thiopyran-2-carboxylate (4.95 g, 28.0 mmol) andsodium methoxide (1.5 g, 28.0 mmol). The mixture was stirred at 85° C.for 16 h. The ethanol was removed under vacuum and the residue wasdiluted with water and extracted with methylene chloride. The organiclayers were dried over anhydrous sodium sulfate, filtered and thefiltrate was concentrated. The residue was diluted with hexanes and thesolid was filtered to afford the title compound (2.9 g, 44%) as a whitesolid. MW=236.33. ¹H NMR (CDCl₃, 500 MHz) δ 11.41 (s, 1H), 3.13-2.99 (m,1H), 2.99-2.94 (m, 2H), 2.81-2.70 (m, 2H), 2.21-2.14 (m, 2H), 2.14-2.04(m, 2H), 1.92-1.79 (m, 4H), 1.73-1.64 (m, 2H); APCI MS m/z 237 [M+H]⁺.

Step 2. Preparation of2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate

To a suspension of2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (2.9 g,12.3 mmol) in methylene chloride (100 mL) at 0° C. was addedN,N-dimethylaminopyridine (0.020 g, cat.), triethylamine (3.5 mL, 24.6mmol) and trifluoromethanesulfonic acid (2.3 mL, 13.5 mmol). Thesuspension was warmed to rt and stirred for 3 h. The mixture was cooledto 0° C. and the reaction was quenched with a saturated solution ofNaHCO₃. The organic layer was washed a saturated solution of NaHCO₃ andbrine. The organic layers were dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (3.40 g, 75%) as a yellow solid. MW=368.40. ¹H NMR(CDCl₃, 500 MHz) δ 3.28-3.20 (m, 1H), 3.10-3.05 (m, 1H), 2.98 (t, J=6.5Hz, 2H), 2.31-2.24 (m, 2H), 2.09-1.99 (m, 2H), 1.89-1.76 (m, 4H),1.70-1.62 (m, 2H); APCI MS m/z 369 [M+H]⁺.

EXAMPLE 2832-(4-((2-Cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)ethanol

Following general procedure H,2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.200 g, 0.54 mmol) was reacted with2-(4-aminophenyl)ethanol (0.088 g, 0.65 mmol) to afford the desiredproduct (0.081 g, 42%) as a white solid. MW=355.50. ¹H NMR (DMSO-d₆, 500MHz) δ 7.81 (s, 1H), 7.57 (d, J=8.5 Hz, 2H), 7.12 (d, J=8.5 Hz, 2H),4.59 (t, J=5.5 Hz, 1H), 3.62-3.55 (m, 2H), 3.12-3.07 (m, 2H), 3.00(quin, J=8.0 Hz, 1H), 2.75 (t, J=6.5 Hz, 2H), 2.68 (t, J=7.0 Hz, 2H),2.15-2.08 (m, 2H), 1.94-1.86 (m, 2H), 1.81-1.65 (m, 4H), 1.62-1.53 (m,2H); APCI MS m/z 356 [M+H]⁺.

EXAMPLE 2842-(4-((2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure H,2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.133 g, 0.36 mmol) was reacted with2-(4-aminophenyl)acetamide (0.063 g, 0.43 mmol) to afford the titlecompound (0.072 g, 54%) as an off-white solid. MW=368.50. ¹H NMR(DMSO-d₆, 300 MHz) δ 7.91 (s, 1H), 7.59 (d, J=8.5 Hz, 2H), 7.44 (s, 1H),7.16 (d, J=8.5 Hz, 2H), 3.31 (s, 2H), 3.13-3.07 (m, 2H), 3.00 (quin,J=8.0 Hz, 1H), 2.75 (t, J=6.5 Hz, 2H), 2.17-2.06 (m, 2H), 1.97-1.48 (m,8H); APCI MS m/z 369 [M+H]⁺.

EXAMPLE 2852-Cyclopentyl-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Step 1. Preparation of2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate

To a solution of2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (2.9 g, 7.88 mmol) in methylene chloride (100mL) was added MCBPA (77%, 5.3 g, 23.6 mmol). The reaction stirred at rtfor 16 h. The mixture was diluted with methylene chloride and washedwith water, a saturated solution of Na₂S₂O₃, a saturated solution ofNaHCO₃, and brine. The organic layers were dried over anhydrous sodiumsulfate, filtered, and the filtrate was concentrated to afford crudeproduct (1.9 g) as a light brown gum. Crude product was contaminatedwith the hydrolyzed material(2-cyclopentyl-4-hydroxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide). MW=400.39. APCI MS m/z 401 [M+H]⁺.

EXAMPLE 2852-Cyclopentyl-4-((4-(2-hydroxyethyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Following general procedure H,2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.200 g, crude) was reacted with2-(4-aminophenyl)ethanol (0.034 g, 0.25 mmol) to afford the titlecompound (0.040 g, 20%) as a white solid. MW=387.50. ¹H NMR (DMSO-d₆,500 MHz) δ 8.57 (s, 1H), 7.52 (d, J=8.5 Hz, 2H), 7.21 (d, J=8.5 Hz, 2H),4.62 (t, J=5.5 Hz, 1H), 3.70-3.65 (m, 2H), 3.63-3.57 (m, 2H), 3.09(quin, J=8.0 Hz, 1H), 2.93 (t, J=6.5 Hz, 2H), 2.71 (t, J=7.0 Hz, 2H),2.37-2.29 (m, 2H), 1.99-1.90 (m, 2H), 1.83-1.54 (m, 6H); APCI MS m/z 388[M+H]⁺.

EXAMPLE 2862-(4-((2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)amino)phenyl)acetamide

Following general procedure H,2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.200 g, crude) was reacted with2-(4-aminophenyl)acetamide (0.038 g, 0.25 mmol) to afford the titlecompound (0.055 g, 27%) as a white solid. MW=400.49. ¹H NMR (DMSO-d₆,500 MHz) δ 8.60 (s, 1H), 7.55 (d, J=8.5 Hz, 2H), 7.44 (s, 1H), 7.25 (d,J=8.5 Hz, 2H), 6.87 (s, 1H), 3.71-3.64 (m, 2H), 3.36 (s, 2H), 3.10(quin, J=8.0 Hz, 1H), 2.94 (t, J=6.5 Hz, 2H), 2.38-2.29 (m, 2H),1.99-1.91 (m, 2H), 1.84-1.55 (m, 6H); APCI MS m/z 401 [M+H]⁺.

EXAMPLE 2872-Cyclopentyl-4-((4-(3-hydroxypropyl)phenyl)amino)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Following general procedure H,2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yltrifluoromethanesulfonate (0.215 g, crude) was reacted with3-(4-aminophenyl)propan-1-ol (0.040 g, 0.26 mmol) to afford the titlecompound (0.018 g, 17%) as a white solid. MW=401.52. ¹H NMR (DMSO-d₆,500 MHz) δ 8.56 (s, 1H), 7.51 (d, J=8.5 Hz, 2H), 7.19 (d, J=8.5 Hz, 2H),4.44 (t, J=5.5 Hz, 1H), 3.70-3.65 (m, 2H), 3.45-3.38 (m, 2H), 3.09(quin, J=8.0 Hz, 1H), 2.93 (t, J=6.5 Hz, 2H), 2.63-2.57 (m, 2H),2.36-2.28 (m, 2H), 1.99-1.90 (m, 2H), 1.83-1.55 (m, 8H); APCI MS m/z 402[M+H]⁺.

EXAMPLE 2882-Cyclopentyl-4-(4-(2-hydroxyethyl)benzyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Step 1. Preparation of4-chloro-2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

To mixture of2-cyclopentyl-4-hydroxy-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide (0.650 g, 2.42 mmol) in dichloroethane (10 mL) was addedphosphorous trichloride (1.35 mL, 14.5 mmol). The mixture was stirred at65° C. for 24 h. The reaction was quenched into a mixture of methylenechloride and a saturated solution of NaHCO₃ and extracted with methylenechloride. The organic layers were dried over anhydrous sodium sulfate,filtered, and the filtrate was concentrated. The residue was purified bycolumn chromatography (silica, hexanes/ethyl acetate) to afford thetitle compound (0.150 g, 22%) as a tan solid. MW=286.78. ¹H NMR (CDCl₃,500 MHz) δ 3.49-3.42 (m, 2H), 3.31 (p, J=8.0 Hz, 1H), 3.11 (t, J=6.2 Hz,2H), 2.53-2.45 (m, 2H), 2.13-2.04 (m, 2H), 1.94-1.78 (m, 4H), 1.75-1.65(m, 2H); APCI MS m/z 287 [M+H]⁺.

Step 2. Preparation of methyl2-(4-((2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate

Following general procedure H,4-chloro-2-cyclopentyl-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide (0.150 g, 0.52 mmol) was reacted with methyl2-(4-((4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methyl)phenyl)acetate(0.152 g, 0.52 mmol) to afford the title compound (0.099 g, 46%) as alight yellow oil. MW=414.52. ¹H NMR (CDCl₃, 500 MHz) δ 7.45 (d, J=8.0Hz, 2H), 7.20 (d, J=8.0 Hz, 2H), 4.50 (s, 2H), 3.67 (s, 3H), 3.58 (s,2H), 3.44-3.40 (m, 2H), 3.27 (quin, J=8.0 Hz, 1H), 3.06 (t, J=6.2 Hz,2H), 2.48-2.42 (m, 2H), 2.04-1.97 (m, 2H), 1.88-1.73 (m, 4H), 1.70-1.62(m, 2H); APCI MS m/z 415 [M+H]⁺.

EXAMPLE 2882-Cyclopentyl-4-(4-(2-hydroxyethyl)benzyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidine5,5-dioxide

Following general procedure E1, methyl2-(4-((2-cyclopentyl-5,5-dioxido-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl)methyl)phenyl)acetate (0.060 g, 0.14 mmol) wasreacted with DIBAL (1.0 M, 0.58 mL, 0.58 mmol) to afford the titlecompound (0.040 g, 71%) as a white solid. MW=386.51. ¹H NMR (DMSO-d₆,500 MHz) δ7.26 (d, J=8.5 Hz, 2H), 7.11 (d, J=8.5 Hz, 2H), 4.58 (t, J=5.5Hz, 1H), 4.38 (s, 2H), 3.69-3.62 (m, 2H), 3.59-3.52 (m, 2H), 3.23 (quin,J=8.0 Hz, 1H), 3.06 (t, J=6.5 Hz, 2H), 2.66 (t, J=7.0 Hz, 2H), 2.33-2.25(m, 2H), 2.00-1.91 (m, 2H), 1.81-1.56 (m, 6H); APCI MS m/z 387 [M+H]⁺.

EXAMPLE 2892-(3-Chlorophenyl)-4-(4-methylbenzyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride

A 20-mL vial, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.200g, 1.20 mmol), Pd(dppf)Cl₂ (0.062 g, 0.076 mmol) and THF (4.0 mL) at rtunder nitrogen. A solution of 4-methylbenzylzinc chloride (2.3 mL, 0.5Min THF, 1.14 mmol) was added. The reaction mixture was placed underargon and stirred at 80° C. for 23 h. until the starting chloride wasconsumed. The cooled reaction was absorbed onto silica and purified bychromatography on silica gel using hexanes/ethyl acetate as the eluentfollowed by chromatography on silica gel using hexanes/dichloromethaneas the eluent, to afford the free base of the title compound (0.104 g,41% yield) as an oil. MW=333.85. ¹H NMR (CDCl₃, 500 MHz) δ 7.93-7.91 (m,1H), 7.76 (dt, J=7.0, 1.5 Hz, 1H), 7.36-7.30 (m, 2H), 7.24 (s, 1H), 7.11(d, J=8.0 Hz, 2H), 7.06 (d, J=8.0 Hz, 2H), 3.91 (s, 2H), 3.07 (t, J=7.5Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 2.33 (s, 3H), 2.13 (quin, J=7.5 Hz,2H). Treatment with 1.25M HCl in methanol (0.38 mL, 0.47 mmol) afforded2-(3-chlorophenyl)-4-(4-methylbenzyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (0.108 g, 38%) as a white solid. MW=370.31. M.p. 44-46° C.¹H NMR (DMSO-d₆, 500 MHz) δ 8.10-8.07 (m, 1H), 7.98-7.93 (m, 1H), 7.81(s, 1H), 7.57-7.50 (m, 2H), 7.17 (d, J=8.0 Hz, 2H), 7.11 (d, J=8.0 Hz,2H), 4.60 (br s, 1H), 4.01 (s, 2H), 3.04 (t, J=7.5 Hz, 2H), 2.87 (t,J=7.5 Hz, 2H), 2.25 (s, 3H), 2.09 (quin, J=7.5 Hz, 2H); ESI MS m/z 334[M+H]⁺.

EXAMPLE 2902-(3-Chlorophenyl)-N-(4-fluorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-aminehydrochloride

A 10-mL microwave vial was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridine (0.072g, 0.27 mmol), 4-fluoroaniline (0.052 mL, 0.54 mmol) and conc. HCl (1drop) in NMP (2 mL). The resulting mixture was heated at 120° C. undermicrowave irradiation for 3 h. After this time, the reaction mixture wascooled, diluted with water (25 mL) then treated with saturated sodiumbicarbonate until pH ˜8 and extracted with ethyl acetate. The combinedextract was washed with saturated sodium chloride, dried over sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by chromatography on silica using hexanes/ethyl acetate(10:0 to 1:1) as the eluent to afford the free base of the titlecompound (0.064 g, 70%) as an oil. MW=338.81. ¹H NMR (DMSO-d₆, 500 MHz)δ 8.14 (s, 1H), 7.93-7.90 (m, 1H), 7.76 (dt, J=7.0, 2.0 Hz, 1H),7.45-7.39 (m, 2H), 7.31-7.26 (m, 2H), 7.24-7.18 (m, 2H), 7.13 (s, 1H),2.91 (t, J=7.5 Hz, 2H), 2.82 (t, J=7.5 Hz, 2H), 2.09 (quin, J=7.5 Hz,2H). Treatment with 1.25M HCl in methanol (0.15 mL, 0.19 mmol, 1.0 eq.)afforded the title compound (0.064 g, 91%) as a white solid. MW=375.27.M.p. 103-106° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 13.99 (br s, 1H), 9.05 (brs, 1H), 7.92-7.89 (m, 1H), 7.75-7.70 (m, 1H), 7.57-7.49 (m, 2H),7.41-7.35 (m, 2H), 7.31-7.25 (m, 2H), 7.04 (s, 1H), 3.04 (t, J=7.5 Hz,2H), 2.87 (t, J=7.5 Hz, 2H), 2.17 (quin, J=7.5 Hz, 2H); ESI MS m/z 339[M+H]⁺.

EXAMPLE 2912-(4-((3-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetonitrilehydrochloride

Step 1. Preparation of2-(3-chlorophenyl)-N-(diphenylmethylene)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

A 20-mL vial, with stirrer bar, was charged with4-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridinehydrochloride (1.00 g, 3.33 mmol), benzophenone imine (0.56 mL, 3.66mmol), Pd(dba)₂ (0.057 g, 0.10 mmol, 0.03 eq.),1,3-bis(2,6-di-iso-propylphenyl)imidazolium chloride (0.042 g, 0.10mmol) and potassium tert-butoxide (0.93 g, 8.32 mmol) in dioxane (12 mL)at rt. The reaction mixture was placed under argon and stirred at 100°C. for 24 h. The cooled reaction was diluted with ethyl acetate (150 mL)and washed with saturated sodium chloride (2×25 mL). The organic layerwas dried over sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by chromatography on silica gel usinghexanes/ethyl acetate (10:0 to 8:2) as the eluent to afford the titlecompound (0.47 g, 34%) as a yellow solid. MW=408.92. ¹H NMR (CDCl₃, 500MHz) δ 7.85-7.70 (m, 3H), 7.69-7.63 (m, 1H), 7.56-7.39 (m, 3H),7.36-7.26 (m, 5H), 7.22-7.10 (m, 2H), 6.81 (s, 1H), 2.97 (t, J=7.5 Hz,2H), 2.62 (t, J=7.5 Hz, 2H), 2.07-1.98 (m, 2H); ESI MS m/z 409 [M+H]⁺.

Step 2. Preparation of2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

A 250-mL round bottom flask was charged with2-(3-chlorophenyl)-N-(diphenylmethylene)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine(0.47 g, 1.15 mmol) and 2N aqueous HCl (12 mL, 24 mmol) in THF (50 mL).After 18 h at rt, the resultant solution was concentrated under reducedpressure. The solid residue was washed with 2N aqueous HCl (10 mL) thendiethyl ether. The solid and aqueous layers were combined diluted withethyl acetate then treated with 2N aqueous NaOH. The aqueous layer wasextracted with ethyl acetate. The combined ethyl acetate extract waswashed with saturated sodium chloride (5 mL), dried over sodium sulfate,filtered and concentrated under reduced pressure to afford the titlecompound (0.25 g, 89%) as a white solid. MW=244.72. ¹H NMR (DMSO-d₆, 500MHz) δ 7.92 (t, J=7.0 Hz, 1H), 7.81 (dt, J=7.5, 1.5 Hz, 1H), 7.44 (t,J=8.0 Hz, 1H), 7.41-7.38 (m, 1H), 6.86 (s, 1H), 5.86 (s, 2H), 2.82 (t,J=7.5 Hz, 2H), 2.68 (t, J=7.5 Hz, 2H), 2.02 (quin, J=7.5 Hz, 2H).

Step 3. Preparation of3-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine

A 25-mL round bottom flask was charged with2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine (0.250 g,1.02 mmol) in DMF (6 mL). N-Chlorosuccinimide (0.136 g, 1.02 mmol) wasadded at rt and the resultant solution was stirred for 3 h. FurtherN-chlorosuccinimide (0.036 g, 0.27 mmol) was added and the reaction wasstirred for 2 h. The reaction was diluted with water (100 mL) and ethylacetate (50 mL). The layers were separated and the aqueous layerextracted with ethyl acetate (2×25 mL). The combined extract acetateextract was washed with saturated sodium chloride (2×10 mL), dried oversodium sulfate, filtered and concentrated under reduced pressure. Theresidue was purified by chromatography on silica gel using hexanes/ethylacetate (10:0 to 9:1) as the eluent to afford the title compound (0.110g, 38%) as a white solid. MW=279.16. ¹H NMR (CD₃, 500 MHz) δ 7.62-7.59(m, 1H), 7.52-7.48 (m, 1H), 7.37-7.32 (m, 2H), 4.54 (s, 2H), 2.99 (t,J=7.5 Hz, 2H), 2.80 (t, J=7.5 Hz, 2H), 2.21 (quin, J=7.5 Hz, 2H); ESI MSm/z 279 [M+H]⁺.

EXAMPLE 2912-(4-((3-Chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-yl)amino)phenyl)acetonitrilehydrochloride

A 20-mL vial, with stirrer bar, was charged with3-chloro-2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[b]pyridin-4-amine(0.110 g, 0.39 mmol), (4-bromophenyl)acetonitrile (0.085 g, 0.43 mmol),Pd₂(dba)₃ (0.011 g, 12 mmol), X-Phos (0.021 g, 0.043 mmol) and potassiumphosphate (0.125 g, 0.49 mmol) in toluene (4 mL) at rt. The reactionmixture was placed under argon and stirred at 100° C. for 30 h. Afterthis time, additional (4-bromophenyl)acetonitrile (0.085 g, 0.43 mmol),Pd₂(dba)₃ (0.011 g, 0.012 mmol) and X-Phos (0.021 g, 43 mmol) in toluene(1 mL) were added. After a further 16 h, an additional solution of(4-bromophenyl)acetonitrile (0.085 g, 0.43 mmol), Pd₂(dba)₃ (0.011 g,0.012 mmol) and X-Phos (0.021 g, 43 mmol) in toluene (1 mL) was addedand the reaction stirred for 23 h. The cooled reaction was filteredthrough celite and concentrated under reduced pressure. The residue waspurified by chromatography on silica using hexanes/ethyl acetate (10:0to 0:10) as the eluent followed by chromatography on silica usinghexanes/ethyl acetate (10:0 to 1:1) as the eluent to afford the freebase of the title compound (0.041 g, 26%) as an oil. MW=394.30. ESI MSm/z 394 [M+H]⁺. Treatment with 1.25M HCl in methanol (0.12 mL, 0.15mmol, 1.5 eq.) followed by recrystallization from acetonitrile/waterafforded the title compound (0.016 g, 38%) as an off-white solid.MW=430.76. M.p. 206-208° C. ¹H NMR (DMSO-d₆, 500 MHz) δ 8.70 (br s, 1H),7.67 (s, 1H), 7.65-7.52 (m, 3H), 7.36-7.26 (m, 2H), 7.15-7.01 (m, 2H),4.04 (s, 2H), 2.89 (t, J=7.5 Hz, 2H), 2.34-2.25 (m, 2H), 1.96 (quin,J=7.5 Hz, 2H); ESI MS m/z 395 [M+H]⁺.

EXAMPLE 292[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]boronicacid

Step 1. [2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate

A 18-mL vial was charged with2-(5-chloro-2-thienyl)-5-ethyl-4-methyl-1H-pyrimidin-6-one (254 mg, 1mmol, 1 eq., preparation described in EXAMPLE 71) andN,N-diisopropylethylamine (440 mg, 3.4 mmol, 3.4 eq.). Dichloromethane(6 ml, DCM) was added. To the mixture at 0° C. was added a solution oftriflic anhydride in dichloromethane (1M, 1.5 ml, 1.5 eq.) dropwise by asyringe. After the addition was complete, the mixture was stirred at 0°C.˜rt for 1 hr. The mixture was then poured into NaHCO₃ aq. (20 ml). Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (15 ml). The organics were combined and dried overNa₂SO₄. The volatile material was removed and the crude material waspurified by chromatography on silica gel using hexane/DCM (9:1 then 4:1)as eluent to afford the title compound as white solid (337 mg, 87%yield).

Step 2.2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-4-amine

A 18-mL vial was charged with[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]trifluoromethanesulfonate (39 mg, 0.1 mmole) and4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (22 mg, 0.1 mmol)and DMSO (0.5 ml). The resulting mixture was stirred under Ar for 3.5hr. After cooling to room temperature, water was added to the mixture (5ml). The precipitate was collected by filtration and the crude productwas purified by chromatography on silica gel using hexane/DCM (4:1)followed by 2% of methanol in DCM as eluent to afford the titlecompound, containing impurities, which was forward to the next stepwithout any further purification (10.3 mg, 23% yield).

Step 3.[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]boronicacid

A 18-mL vial was charged with2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]pyrimidin-4-amine(10.3 mg, 0.023 mmol) and potassium hydrogen difluoride (40 mg, 0.5mmol). Water (0.2 ml) and MeOH (1 ml) were added respectively. Theresulting mixture was stirred at rt for 1 hr. Then the volatile materialwas removed under reduced pressure. The residue was treated withtrimethylsilyl chloride (0.1 ml) in a mixture of acetonitrile (1 ml) andwater (0.2 ml). After the mixture was stirred at rt for 1 hr, thevolatile material was removed the residue was treated with NaHCO₃ aq. (5ml). The precipitate was collected and purified by Preparative TLC plateusing 5% of acetone in DCM as mobile phase to give the title compound (2mg, 23% yield). MW=373.66. ¹H NMR (Methanol-d₄, 400 MHz) δ 7.87 (d,J=8.4 Hz, 2H), 7.74 (d, J=8.4 Hz, 2H), 7.67 (d, J=4.0 Hz, 1H), 6.93 (d,J=4.0 Hz, 1H), 2.67 (q, J=7.6 Hz, 2H), 2.54 (s, 3H), 1.21 (t, J=7.6 Hz,3H).

EXAMPLE 2932-(5-Chloro-2-thienyl)-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (5mg, 34% yield). MW=383.66. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.72(m, 2H), 7.48 (d, J=8.0 Hz, 1H), 6.96 (d, J=4.0 Hz, 1H), 6.40 (br, 1H),5.18 (s, 2H), 3.03 (t, J=7.2 Hz, 2H), 2.84 (t, J=7.2 Hz, 2H), 2.23 (m,2H).

EXAMPLE 2942-(3-Chlorophenyl)-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(10 mg, 69% yield). MW=377.63. ¹H NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H),8.31 (d, J=8.4 Hz, 1H), 8.06 (s, 1H), 7.76 (d, J=8.0 Hz, 1H), 7.50 (d,J=8.0 Hz, 1H), 7.43 (m, 2H), 6.46 (br, 1H), 5.18 (s, 2H), 3.09 (t, J=7.2Hz, 2H), 2.89 (t, J=7.2 Hz, 2H), 2.26 (m, 2H).

EXAMPLE 2952-(4-Chlorophenyl)-N-(1-hydroxy-3H-2,1-benzoxaborol-5-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (6mg, 41% yield). MW=377.63. ¹H NMR (400 MHz, DMSO-D₆) δ 9.01 (brs, 1H),8.31 (d, J=8.8 Hz, 2H), 7.94 (s, 1H), 7.71 (brs, 2H), 7.56 (d, J=8.8 Hz,2H), 5.04 (s, 2H), 2.92 (m, 4H), 2.11 (m, 2H).

EXAMPLE 2962-[4-[[2-(5-Chloro-2-thienyl)-6-(trifluoromethyl)pyrimidin-4-yl]amino]phenyl]aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (1mg, 3.5% yield). MW=410.80. ¹H NMR (400 MHz, Methanol-D₄) δ 7.81 (d,J=4.0 Hz, 1H), 7.70 (brs, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.07 (d, J=4.0Hz, 1H), 6.89 (s, 1H), 3.64 (s, 2H).

EXAMPLE 2972-[4-[[2-(5-Chloro-2-thienyl)-6-cyclopropyl-pyrimidin-4-yl]amino]phenyl]aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (9mg, 14% yield). MW=385.87. ¹H NMR (400 MHz, DMSO-D₆) δ 12.3 (brs, 1H),9.55 (brs, 1H), 7.65-7.20 (m, 3H), 7.25 (d, J=8.4 Hz, 2H), 7.18 (d,J=4.0 Hz, 1H), 6.54 (s, 1H), 3.53 (s, 2H), 1.98 (m, 1H), 1.01-0.97 (m,4H).

EXAMPLE 2982-(5-Chloro-2-thienyl)-6-cyclopropyl-N-[4-(1H-tetrazol-5-ylmethyl)phenyl]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(16 mg, 84% yield, HCl salt). MW/HCl=446.40. ¹H NMR (400 MHz, DMSO-D₆) δ9.69 (brs, 1H), 7.66 (m, 3H), 7.27 (d, J=8.8 Hz, 2H), 7.19 (d, J=4.0 Hz,1H), 4.26 (s, 2H), 2.0 (m, 1H), 1.00 (m, 4H).

EXAMPLE 2992-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(pyrazol-1-ylmethyl)phenyl]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(12 mg, 27% yield, HCl salt). MW=446.60. ¹H NMR (400 MHz, DMSO-D₆) δ 7.9(brs, 1H), 7.68 (d, J=4.0 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.48 (d,J=4.0 Hz, 1H), 7.27 (m, 3H), 6.29 (m, 1H), 5.35 (s, 2H), 2.72 (q, J=7.2Hz, 2H), 2.52 (s, 3H), 1.11 (t, J=7.2 Hz, 3H).

EXAMPLE 3002-(5-Chloro-2-thienyl)-N-[4-(1,3-dihydrotriazol-2-ylmethyl)phenyl]-5-ethyl-6-methyl-pyrimidin-4-amine

Step 1:2-[(4-Nitrophenyl)methyl]triazole

A 18-mL vial was charged with 1-(chloromethyl)-4-nitro-benzene (500 mg,3 mmol, 1 eq.), triazole (310 mg, 4.5 mmol, 1.5 eq.), potassiumcarbonate (1.24 g, 9 mmol, 3 eq.) and DMF (5 ml). After the resultingmixture was stirred at rt overnight, water (20 ml) was added. Theprecipitate was collected by filtration and washed with small amount ofwater. After drying, 340 mg of the title compound was obtained as amixture of two regioisomers (340 mg, 55% yield).

Step 2: 4-(Triazol-2-ylmethyl)aniline

A 25-mL round bottomed flask was charged with2-[(4-nitrophenyl)methyl]triazole (195 mg, 0.95 mmol, 1 eq.), palladiumon carbon (206 mg, 10 wt. % loading, 0.2 eq.) and ethanol (3 ml). Theresulting mixture was stirred under H₂ over night. The mixture waspassed through a plug of celite and washed with methanol (5 ml). Removalof solvent under reduced pressure gave the crude product (160 mg, tworegioisomers, 97% yield). The product thus obtained was forwarded to thenext step without any further purification.

Step 3:2-(5-Chloro-2-thienyl)-N-[4-(1,3-dihydrotriazol-2-ylmethyl)phenyl]-5-ethyl-6-methyl-pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(12 mg, 20% yield, only one isomer was isolated). MW=412.94. ¹H NMR (400MHz, CDCl₃) δ 7.70-7.61 (m, 5H), 7.38 (d, J=8.8 Hz, 2H), 6.93 (d, J=4.0Hz, 1H), 6.58 (brs, 1H), 5.63 (s, 2H), 2.62 (q, J=7.6 Hz, 2H), 2.49 (s,3H), 1.21 (t, J=7.6 Hz, 3H).

EXAMPLE 3012-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide

Step1:2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]aceticacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(271 mg, 37% yield).

Step2:2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide

A 8-mL vial was charged with2-[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]aceticacid (30 mg, 0.077 mmol, 1 eq.), cyamide (30 mg, 0.71 mmol, 9 eq.), HATU(44 mg, 0.16 mmol, 1.5 eq.), diisopropylethylamine (35 mg, 0.27 mmol,3.5 eq.) and DMF (0.5 ml). The resulting mixture was stirred at rtovernight until the starting acid was consumed. The mixture was added toNaHCO₃ aq. (5 ml) and extracted with ethyl acetate (5 ml×3). The organiclayers were combined and dried over Na₂SO₄. Removal of solvent gave aresidue, which was purified by chromatography on silica gel using 0.5-3%of MeOH in DCM as eluent to give the title compound as a white solid (16mg, 50% yield). MW=411.91. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (brs, 1H),7.67 (d, J=8.8 Hz, 2H), 7.55 (d, J=4.0 Hz, 1H), 7.24 (d, J=8.8 Hz, 2H),7.15 (d, J=4.0 Hz, 1H), 5.77 (s, 2H), 2.74 (q, J=7.6 Hz, 2H), 2.40 (s,3H), 1.20 (t, J=7.6 Hz, 3H).

EXAMPLE 3023-[[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-4H-1,2,4-oxadiazol-5-one

Step1:2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-hydroxy-acetamidine

A 50-mL round bottomed flask was charged with2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]acetonitrile(120 mg, 0.325 mmol, 1 eq.), NH₂OH/HCl (160 mg, 2.3 mmol, 7 eq), K₂CO₃(320 mg, 2.3 mol, 7 eq.), EtOH (10 ml) and water (1 ml). The mixture wasstirred under reflux overnight. After cooling to room temperature, thevolatile material was removed under reduced pressure. The residue waspurified by chromatography on silica gel using 1.5-4% of methanol indichloromethane as eluent to give the title compound (61 mg, 47% yield).

Step 2:Phenyl(NE)-N-[2-[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-1-(hydroxyamino)ethylidene]carbamate

A 18-mL vial was charged with2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-hydroxy-acetamidine(61 mg, 0.15 mmol), phenyl chloroformate (29 mg, 0.18 mmol, 1.2 eq.),Et₃N (20 mg, 0.2 mmol, 1.3 eq.) and dichloromethane (5 ml). The mixturewas stirred at OC˜rt until starting material was consumed (4 hr). Themixture was poured into saturated sodium bicarbonate solution (10 ml)and extracted with dichloromethane (3×5 ml). The organic layers werecombined and dried over Na₂SO₄. Removal of solvent under reducedpressure gave the title compound (80 mg, 100% yield). The product thusobtained was forwarded to the next step without any purification.

Step 3:3-[[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-4H-1,2,4-oxadiazol-5-one

A 50-mL round bottomed flask was charged with Phenyl(NE)-N-[2-[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-1-(hydroxyamino)ethylidene]carbamate(80 mg, 0.15 mmol) and toluene (10 ml). The mixture was stirred underreflux overnight. After cooling to room temperature, the volatilematerial was removed under reduced pressure and the residue was purifiedby chromatography on silica gel using 1-2% methanol in dichloromethaneas eluent to give the title compound as a white solid (16 mg, 25% yieldover two steps). MW=427.91. ¹H NMR (400 MHz, DMSO-d₆) δ 12.4 (brs, 1H),8.57 (brs, 1H), 7.73 (d, J=8.4 Hz, 2H), 7.56 (d, J=3.6 Hz, 1H), 7.29 (d,J=8.4 Hz, 2H), 7.15 (d, J=3.6 Hz, 1H), 3.86 (s, 2H), 2.73 (q, J=7.6 Hz,2H), 2.40 (s, 3H), 1.10 (t, J=7.6 Hz, 3H).

EXAMPLE 3032-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-3-hydroxy-cyclopent-2-en-1-one

Step 1:4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzaldehyde

A 50-mL round bottomed flask was charged with4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzonitrile(130 mg, 0.366 mmol), toluene (6 ml) and dichloromethane (12 ml). Themixture was added DIBAL-H (1 ml, 1M in DCM, 1 mmol, 2.73 eq.) dropwiseby a syringe at 0° C. After the addition was complete, the mixture wasallowed to warm to room temperature overnight. Then the mixture wasadded 2N HCl aq. (2 ml). The volatile material was removed under reducedpressure and the residue was partitioned between ethyl acetate (10 ml)and sodium bicarbonate (10 ml). The organic layer was separated anddried over Na₂SO₄. Removal of solvent gave the title compound as a solid(165 mg, 100% yield). The product thus obtained was forwarded to thenext step without any further purification.

Step2:2-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-3-hydroxy-cyclopent-2-en-1-one

A 18-mL vial was charged with4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]benzaldehyde(139 mg, 0.39 mmol, 1 eq.),trimethyl-(2-trimethylsilyloxycyclobuten-1-yl)oxy-silane (140 mg, 0.6mmol, 1.53 eq.), and dichloromethane (2 ml). To the mixture was addedBF₃/Et₂O (80 μL, 0.63 mmol, 1.6 eq.). The mixture was stirred at roomtemperature overnight and then added to sodium bicarbonate solution (10ml). The mixture was extracted with ethyl acetate (3×5 ml). The organiclayers were combined and dried over Na₂SO₄. Removal of solvent gave aresidue, which was purified by chromatography on silica gel using 2-3%of methanol in dichloromethane as eluent to give the title compound as asolid (22 mg, 13% yield). MW=425.93. ¹H NMR (400 MHz, DMSO-d₆) δ 12.4(brs, 1H), 8.52 (brs, 1H), 7.92 (d, J=8.8 Hz, 2H), 7.67 (d, J=8.8 Hz,2H), 7.56 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 3.34 (m, 4H), 2.73(q, J=7.2 Hz, 2H), 2.40 (s, 3H), 1.11 (t, J=7.2 Hz, 3H).

EXAMPLE 304N-[4-[(4-Chloropyrazol-1-yl)methyl]phenyl]-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(12 mg, 23% yield). MW=444.38. ¹H NMR (400 MHz, CDCl₃) δ 7.71 (d, J=8.8Hz, 2H), 7.66 (d, J=4.0 Hz, 1H), 7.49 (s, 1H), 7.39 (s, 1H), 7.30 (d,J=8.8 Hz, 2H), 6.93 (d, J=4.0 Hz, 1H), 6.55 (brs, 1H), 5.27 (s, 2H),2.65 (q, J=7.6 Hz, 2H), 2.49 (s, 3H), 1.25 (t, J=7.6 Hz, 3H).

EXAMPLE 305 Methyl2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate

Step 1: N-Hydroxy-2-(4-nitrophenyl)acetamidine

A 250-mL round bottomed flask was charged with2-(4-nitrophenyl)acetonitrile (2.5 g, 15.4 mmol, 1 eq.), NH₂OH/HCl (2.12g, 31 mmol, 2 eq), NaHCO₃ (2.82 g, 2.3 mol, 7 eq.), MeOH (100 ml) andwater (16 ml). The mixture was stirred under reflux overnight. Aftercooling to room temperature, the volatile material was removed underreduced pressure. The residue was treated with water (100 ml). Solid wascollected by filtration and washed with water (3×20 ml) followed bydichloromethane (3×10 ml). After drying, the title compound was obtainedas yellowish solid (2.46 g, 84% yield).

Step 2: Methyl 2-[(4-nitrophenyl)methyl]-1H-imidazole-4-carboxylate

A 250-mL round bottomed flask was charged withN-hydroxy-2-(4-nitrophenyl)acetamidine (1 g, 5 mmol, 1 eq.), methylpropiolate (500 mg, 6 mmol, 1.2 eq.) and EtOH (24 ml). The resultingmixture was stirred under reflux for 7 hrs. After cooling to roomtemperature, the volatile material was removed under reduced pressureand the residue was added phenyl ether (200 ml). The mixture was stirredat 190° C. for 30 minutes. After cooling to room temperature, themixture was poured into hexane (1 L). Solid was collected and washedwith hexane. The crude product thus obtained (964 mg) was purified bychromatography on silica gel using 10-20% acetone in dichloromethane aseluent to afford the title compound as a gray solid (220 mg, 17% yieldover two steps).

Step 3: Methyl 2-[(4-aminophenyl)methyl]-1H-imidazole-4-carboxylate

A 100-mL round bottomed flask was charged with methyl2-[(4-nitrophenyl)methyl]-1H-imidazole-4-carboxylate (220 mg, 0.84mmol), Pd/C (270 mg, 10 wt %, 0.255 mmol, 0.3 eq.) and EtOH (24 ml). Themixture was stirred under 1 atmosphere of hydrogen overnight. Theinsoluble material was removed by filtration and the organics wasevaporated under reduced pressure to dryness to afford the titlecompound (177 mg, 91% yield). The product thus obtained was forwarded tothe next step without any further purification.

Step 4: Methyl2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate

A 8-mL vial was charged with4-chloro-2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidine (100 mg,0.366 mmol, 1.05 eq.), methyl2-[(4-aminophenyl)methyl]-1H-imidazole-4-carboxylate (81 mg, 0.348 mmol,1 eq.), AcOH (0.8 ml). To the mixture was added 4N HCl in dioxane (4drops using 1 ml of a syringe). The resulting mixture was stirred under110° C. for 2 hrs. After cooling to room temperature, the mixture wasadded to sodium bicarbonate solution (20 ml). The precipitate wascollected by filtration and washed with water then purified bychromatography on silica gel using 1-1.5% of methanol in dichloromethaneas eluent to give the title compound as a foam (79 mg, 48% yield).).MW=467.97. ¹H NMR (400 MHz, CDCl₃) δ 7.65 (m, 4H), 7.30 (m, 2H), 6.93(d, J=3.6 Hz, 1H), 6.54 (brs, 1H), 4.18 (s, 2H), 3.90 (s, 3H), 2.64 (q,J=6.8 Hz, 2H), 2.49 (s, 3H), 1.26 (t, J=6.8 Hz, 3H).

EXAMPLE 3062-[[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylicacid

A 8-mL vial was charged with methyl2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate(8 mg, 0.017 mmol, 1 eq.), LiOH/H2O (19 mg, 0.44 mmol, 26 eq.), THF (1ml), MeOH (0.2 ml) and water (0.2 ml). The resulting mixture was stirredat 55° C. overnight. After cooling to room temperature, the mixture wasadded 2N HCl aq. to pH 6-7. The precipitate was collected by filtrationand washed with water. After drying, the title compound was obtained asa solid (4.8 mg, 62% yield). MW=453.94. ¹H NMR (400 MHz, DMSO-d₆) δ 8.52(brs, 1H), 7.65 (m, 3H), 7.55 (d, J=4.0 Hz, 1H), 7.25 (d, J=8.0 Hz, 2H),7.16 (d, J=4.0 Hz, 1H), 3.97 (s, 2H), 2.73 (q, J=7.2 Hz, 2H), 2.49 (s,3H), 1.09 (t, J=7.2 Hz, 3H).

EXAMPLE 3072-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-propyl-acetamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (8mg, 36% yield). MW=428.98. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (d, J=8.8 Hz,2H), 7.67 (d, J=4.0 Hz, 1H), 7.31 (d, J=8.8 Hz, 2H), 6.93 (d, J=4.0 Hz,1H), 6.55 (brs, 1H), 5.45 (brs, 1H), 3.61 (s, 2H), 3.21 (q, J=6.4 Hz,2H), 2.65 (q, J=7.6 Hz, 2H), 2.50 (s, 3H), 1.49 (m, 2H), 1.26 (t, J=7.6Hz, 3H), 0.88 (t, J=7.2 Hz, 3H).

EXAMPLE 3082-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-methyl-acetamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(14 mg, 67% yield). MW=400.92. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (brs, 1H),7.69 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 6.95 (d, J=4.0 Hz, 1H),6.65 (brs, 1H), 5.45 (brs, 1H), 3.62 (s, 2H), 2.81 (d, J=4.8 Hz, 3H),2.66 (q, J=7.6 Hz, 2H), 2.56 (s, 3H), 1.49 (m, 2H), 1.27 (t, J=7.6 Hz,3H).

EXAMPLE 3092-[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]-N-ethyl-acetamide

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art (7mg, 36% yield). MW=414.95. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (brs, 1H),7.68 (d, J=8.0 Hz, 2H), 7.32 (d, J=8.0 Hz, 2H), 6.96 (d, J=4.0 Hz, 1H),5.45 (brs, 1H), 3.60 (s, 2H), 3.30 (m, 2H), 2.66 (m, 2H), 2.56 (s, 3H),1.27 (t, J=7.2 Hz, 3H), 1.11 (t, J=7.6 Hz, 3H).

EXAMPLE 3102-[[4-[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxamide

A 25-mL round bottomed flask was charged with methyl2-[[4-[[2-(5-chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]phenyl]methyl]-1H-imidazole-4-carboxylate(18 mg, 0.038 mmol) and 2N NH₃ in ethanol (10 ml). The mixture wasstirred under reflux overnight. After cooling to room temperature, thevolatile material was removed under reduced pressure and the residue waspurified by chromatography on silica gel using 10% acetone indichloromethane as eluent to afford the title compound (5.5 mg, 32%yield). MW=452.96. ¹H NMR (400 MHz, CDCl₃) δ 7.68-7.65 (m, 4H), 7.30 (d,J=8.0 Hz, 2H), 6.93 (d, J=4.0 Hz, 1H), 6.54 (brs, 1H), 4.45 (brs, 2H),4.19 (s, 2H), 2.65 (q, J=7.6 Hz, 2H), 2.49 (s, 3H), 1.26 (t, J=7.6 Hz,3H).

EXAMPLE 311[4-[[[2-(5-Chloro-2-thienyl)-5-ethyl-6-methyl-pyrimidin-4-yl]amino]methyl]phenyl]boronicacid

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(7.2 mg, 53% yield). MW=387.69. ¹H NMR (400 MHz, DMSO-d₆) δ 7.94 (s,2H), 7.71 (d, J=8.0 Hz, 2H), 7.61 (t, J=6.0 Hz, 1H), 7.51 (d, J=4.0 Hz,1H), 7.33 (d, J=8.0 Hz, 2H), 7.10 (d, J=4.0 Hz, 1H), 4.61 (d, J=6.0 Hz,2H), 2.55 (q, J=7.2 Hz, 2H), 2.29 (s, 3H), 1.06 (t, J=7.2 Hz, 3H).

EXAMPLE 3122-(5-Chloro-2-thienyl)-N-(2,2-dioxo-1,3-dihydro-2-benzothiophen-5-yl)-5-ethyl-6-methyl-pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(2.5 mg, 15% yield). MW=419.95. ¹H NMR (400 MHz, CDCl₃) δ 7.88 (s, 1H),7.65 (d, J=4.0 Hz, 1H), 7.55 (d, J=8.0 Hz, 1H), 7.33 (d, J=8.0 Hz, 1H),6.94 (d, J=4.0 Hz, 1H), 6.57 (s, 1H), 4.46 (s, 2H), 4.41 (s, 2H), 2.66(q, J=7.2 Hz, 2H), 2.51 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

EXAMPLE 3132-(3-Chlorophenyl)-N-[4-(2H-tetrazol-5-ylmethyl)phenyl]-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-amine

Step 1: Methyl 4-(2-methoxy-2-oxo-ethyl)thiobutanoate

A 250-mL round bottomed flask was charged with methyl sulfanylacetate(15 g, 141 mmol, 1 eq.), methyl 4-chlorobutanoate (20.5 g, 150 mmol,1.06 eq.), sodium methoxide (32.5 g, 25 w % in methanol, 150 mmol, 1.06eq.), sodium iodide (160 mg, 1.06 mmol, 0.0075 eq.) and methanol (75ml). The resulting mixture was stirred under reflux under Ar overnight.After cooling to room temperature, the solvent was removed under reducedpressure, then the residue was dissolved in CH₂Cl₂ (100 mL). Thesolution was washed with H₂O (30 mL), brine (30 mL), and dried withNa₂SO₄. Removal of solvent under reduced pressure gave the titlecompound as an oil (26.12 g, 90% yield). The product thus obtained wasforwarded to the next step without any further purification.

Step 2: Methyl 3-oxotetrahydrothiopyran-2-carboxylate

A 250-mL round bottomed flask was charged with methyl4-(2-methoxy-2-oxo-ethyl)thiobutanoate (26 g, 126 mmol, 1 eq.), sodiummethoxide (30 g, 25 w % in methanol, 139 mmol, 1.1 eq.) and toluene (100ml). The resulting mixture was stirred at 80° C. overnight and thenmethanol was removed by distillation until the temperature of thereaction mixture rose to 106° C. After cooling to room temperature, themixture was poured into a mixture of ice (100 g) and 12N HC (20 mL). Theorganic layer was separated and the aqueous layer was extracted withdichloromethane (3×20 ml) and the combined organic layers were driedover Na₂SO₄. Removal of solvent under reduced pressure gave the titlecompound as an oil (19.3 g, 88% yield). The product thus obtained wasforwarded to the next step without any further purification.

Step 3:2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol

A 100-mL round bottomed flask was charged with methyl3-oxotetrahydrothiopyran-2-carboxylate (1.5 g, 8.6 mmol, 1.47 eq.),3-chlorobenzamidine (HCl salt, 1.1 g, 5.75 mmol, 1 eq.) and ethanol (20ml). The resulting mixture was stirred under reflux for 48 hrs. Aftercooling to room temperature, the volatile material was removed underreduced pressure and the residue was treated with hydrochloric acid (2N,10 ml) and water (20 ml). The precipitate was collected by filtrationand washed with water (3×10 ml) followed by ether (3×10 ml). Afterdrying, the title compound was obtained as white solid (1.15 g, 72%yield).

Step 4:[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate

A 100-mL round bottomed flask was charged with2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-ol (840mg, 3 mmol, 1 eq.), N,N-diisopropylethylamine (1.16 g, 9 mmol, 3 eq.)and dichloromethane (30 ml). To the mixture at 0° C. was added asolution of triflic anhydride in dichloromethane (1M, 4 ml, 1.3 eq.)dropwise by a syringe. After the addition was complete, the mixture wasstirred at 0° C.˜rt for 1 hr. The mixture was then poured into NaHCO₃aq. (20 ml). The organic layer was separated and the aqueous layer wasextracted with dichloromethane (20 ml). The organics were combined anddried over Na₂SO₄. The volatile material was removed and the crudematerial was purified by chromatography on silica gel using hexane/DCM(9:1 then 0:1) as eluent to afford the title compound as white solid(997 mg, 81% yield).

Step 5:2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile

A 8-mL vial was charged with 2-(4-aminophenyl)acetonitrile (40 mg, 0.3mmol, 1.25 eq.),[2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate(100 mg, 0.24 mmol, 1. eq.) and DMF (1 ml). The resulting mixture wasstirred at 70° C. overnight. After cooling to room temperature, waterwas added to the mixture (5 ml). The precipitate was collected byfiltration and washed with water (20 ml). After drying, the crudeproduct was purified by chromatography on silica gel usinghexane/dichloromethane (1:1, 1:1.5 then 1:2) as eluent to give the titlecompound (35 mg, 37% yield).

Step 6:2-(3-Chlorophenyl)-N-[4-(2H-tetrazol-5-ylmethyl)phenyl]-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-amine

A 8-mL vial was charged with2-[4-[[2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile(32 mg, 0.081 mmol, 1 eq.), azido(trimethyl)silane (0.2 ml, excess) andtetrabutylammonium fluoride hydrate (50 mg, 0.19 mmol, 2.3 eq.). Themixture was stirred at 110° C. overnight. After cooling to roomtemperature, the mixture was partitioned between dichloromethane (4 ml)and 2N HCl (4 ml). The solid was collected by filtration and washed withwater (10 ml) followed dichloromethane (10 ml). After drying, the titlecompound was obtained as HCl salt (25 mg, 65% yield).). MW/HCl=472.39.¹H NMR (400 MHz, DMSO-D₆) δ 8.6 (brs, 1H), 8.16 (s, 1H), 8.11 (d, J=7.2Hz, 1H), 7.64 (d, J=8.4 Hz, 2H), 7.53 (m, 2H), 7.29 (d, J=8.4 Hz, 2H),4.31 (s, 2H), 3.21 (d, J=5.6 Hz, 2H), 2.94 (d, J=6.4 Hz, 2H), 2.19 (m,2H).

EXAMPLE 3142-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide

Step 1:2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]aceticacid

A 8-mL vial was charged with[2-(3-chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (100 mg, 0.243 mmol, 1 eq.),2-(4-aminophenyl)acetic acid (37 mg, 0.245 mmol, 1 eq.) and DMSO (1 ml).The resulting mixture was stirred at 110° C. under Ar for 6 hr. Aftercooling to room temperature, water was added to the mixture (15 ml). Theprecipitate was collected by filtration and washed with water (15 ml).After drying, the title compound was obtained (97.5 mg, 97% yield). Theproduct thus obtained was forwarded to the next step without any furtherpurification.

Step 2:2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide

A 8-mL vial was charged with2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]aceticacid (95 mg, 0.23 mmol, 1 eq.), cyamide (15 mg, 0.36 mmol, 1.5 eq.),HATU (130 mg, 0.36 mmol, 1.5 eq.), diisopropylethylamine (90 mg, 0.69mmol, 3 eq.) and DMF (1 ml). The resulting mixture was stirred at rtovernight until the starting acid was consumed. The mixture was added toNaHCO₃ aq. (5 ml) and extracted with ethyl acetate (3×5 ml). The organiclayers were combined and dried over Na₂SO₄. Removal of solvent gave aresidue, which was purified by chromatography on silica gel using apreparation TLC plate and 2% of MeOH in DCM as mobile phase to give thetitle compound as a white solid (20 mg, 20% yield). MW=435.93. ¹H NMR(400 MHz, methanol-d₄) δ 8.19 (s, 1H),), 8.11 (d, J=7.2 Hz, 1H), 7.65(d, J=8.4 Hz, 2H), 7.43 (m, 2H), 7.32 (d, J=8.4 Hz, 2H), 3.69 (s, 2H),3.18 (t, J=5.6 Hz, 2H), 2.94 (d, J=6.4 Hz, 2H), 2.27 (m, 2H).

EXAMPLE 3152-[4-[[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide

A 18-mL vial was charged with2-[4-[[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]-N-cyano-acetamide(19 mg, 0.044 mmol, 1 eq.), oxone (55 mg, 0.18 mmol, 4 eq.), THF (3 ml)and water (3 ml). The clear solution was stirred at room temperatureovernight. The volatile material was removed under reduced pressure andthe residue was treated with sodium bicarbonate solution. Solid wascollected by filtration and washed with water. After drying, the titlecompound was obtained as a white solid (11 mg, 53% yield). MW=467.93. ¹HNMR (400 MHz, methanol-d₄) δ 8.34 (s, 1H),), 8.25 (d, J=7.6 Hz, 1H),7.60 (d, J=8.0 Hz, 2H), 7.49 (m, 2H), 7.39 (d, J=8.0 Hz, 2H), 3.61 (t,J=4.8 Hz, 2H), 3.56 (s, 2H), 3.13 (t, J=6.4 Hz, 2H), 2.54 (m, 2H).

EXAMPLE 3162-(3-Chlorophenyl)-5,5-dioxo-N-[4-(2H-tetrazol-5-ylmethyl)phenyl]-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-amine

Step 1:[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate

A 25-mL round bottomed flask was charged with[2-(3-Chlorophenyl)-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (200 mg, 0.487 mmol, 1 eq.),3-chloroperbenzoic acid (450 mg, 2 mmol, 4 eq.) and dichloromethane (10ml). The resulting mixture was stirred at room temperature until thestarting sulfide was consumed. The mixture was then poured into sodiumbicarbonate solution (20 ml). The organic layer was separated and washedwith sodium bicarbonate solution (10 ml). After drying over Na₂SO₄,solvent was removed under reduced pressure. The residue was purified bychromatography on silica gel using dichloromethane/hexane (1:1, 1.5:1,and 2:1) as eluent to give the title compound as a white solid (137 mg,64% yield).

Step 2:2-[4-[[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile

An 8-mL vial was charged with 2-(4-aminophenyl)acetonitrile (30 mg, 0.23mmol, 2 eq.),[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]trifluoromethanesulfonate (50 mg, 0.112 mmol, 1. eq.) and DMF (0.5 ml).The resulting mixture was stirred at 70° C. overnight. After cooling toroom temperature, water was added to the mixture (5 ml). The precipitatewas collected by filtration and washed with water (10 ml). After drying,the crude product was purified by chromatography on silica gel usingdichloromethane as eluent to give the title compound (18 mg, 38% yield).

Step 3:2-(3-Chlorophenyl)-5,5-dioxo-N-[4-(2H-tetrazol-5-ylmethyl)phenyl]-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-amine

A 8-mL vial was charged with2-[4-[[2-(3-Chlorophenyl)-5,5-dioxo-7,8-dihydro-6H-thiopyrano[3,2-d]pyrimidin-4-yl]amino]phenyl]acetonitrile(17 mg, 0.04 mmol, 1 eq.), azido(trimethyl)silane (0.2 ml, excess) andtetrabutylammonium fluoride hydrate (50 mg, 0.19 mmol, 4.6 eq.). Themixture was stirred at 110° C. overnight. After cooling to roomtemperature, the mixture was partitioned between dichloromethane (8 ml)and 2N HCl (4 ml). The organic layer was separated and washed withsodium bicarbonate solution (5 ml) and dried over Na₂SO₄. Removal ofsolvent under reduced pressure gave a residue, which was purified usinga preparation TLC plate and 3% of methanol in dichloromethane as mobileto give the title compound as white solid (13 mg, 70% yield). MW=467.93.¹H NMR (400 MHz, methanol-d₄) δ 8.32 (s, 1H), 8.24 (d, J=7.2 Hz, 1H),7.67 (d, J=8.4 Hz, 2H), 7.46 (m, 2H), 7.38 (d, J=8.4 Hz, 2H), 4.38 (s,2H), 3.63 (d, J=5.6 Hz, 2H), 3.14 (d, J=6.4 Hz, 2H), 2.54 (m, 2H).

EXAMPLE 3172-(5-chloro-2-thienyl)-5-ethyl-6-methyl-N-[4-(methylsulfonylmethyl)phenyl]pyrimidin-4-amine

The title compound was prepared in a similar manner to those describedherein, with modifications within the skill of one skilled in the art(5.6 mg, 13% yield). MW=421.96. ¹H NMR (400 MHz, CDCl₃) δ 7.80 (d, J=8.8Hz, 2H), 7.68 (d, J=4.0 Hz, 1H), 7.46 (d, J=8.8 Hz, 2H), 6.94 (d, J=4.0Hz, 1H), 6.61 (s, 1H), 4.28 (s, 2H), 2.82 (s, 3H), 2.66 (q, J=7.2 Hz,2H), 2.51 (s, 3H), 1.26 (t, J=7.2 Hz, 3H).

The following compounds may be synthesized using methods analogous tothose described herein and known in the art, using appropriate startingmaterials. These compounds may not yet have been made or tested:

Biological Assays

The activity of many of the compounds in Examples 1-41 and 43-317 asPDE4 inhibitors is illustrated in the following assay. Certain compoundslisted above, which have not yet been made and/or tested, are predictedto have activity in this assay as well.

Kinetic Assay of PDE4 Activity

PDE4 activity may be measured by any method known in the art. Here, akinetic assay of cAMP hydrolysis by purified PDE4 was used, in whichPDE4 activity was measured by coupling the formation of the PDE4reaction product, 5′-adenosine monophosphate, to the oxidation ofreduced nicotinamide adenine dinucleotide (NADH) by the use of threecoupling enzymes (myokinase, pyruvate kinase and lactate dehydrogenase),which allows fluorescent determination of reaction rates. Assays areperformed in 96-well plates in a total volume of 200 μl/well. Compoundsare dissolved in dimethylsulfoxide (DMSO) and added to plates in avolume of 10 μl followed by addition of 165 μl of assay mix. Plates arepre-incubated at 25° C. for 15 min and the reactions are initiated bythe addition of 25 μl of cAMP followed by thorough mixing. Reactionrates are measured by monitoring the decrease in fluorescence usingexcitation at 355 nm and emission at 460 nm for a period of 10 min in afluorescence plate reader. Initial rates (slopes) are determined fromlinear portions of the progress curves. Final concentrations of assaycomponents are as follows: 50 mM Tris, pH 8, 10 mM MgCl₂, 50 mM KCl, 2%DMSO, 5 mM tris(2-carboxyethyl)phosphine (TCEP), 0.4 mMphosphenolpyruvate (PEP), 0.01 mM NADH, 0.04 mM adenosine triphosphate(ATP), 0.004 mM cAMP, 7.5 units myokinase from yeast, 1.6 units pyruvatekinase, 2 units lactate dehydrogenase, and either 0.5 nM human PDE4D7 or10 nM human PDE4B1. All data are percent normalized relative to controlsand are presented as percent inhibition. An inhibitory concentration 50%(IC₅₀) value is calculated by fitting of a sigmoidal dose responsecurve. Human PDE4D7 contained a mutation of serine 54 to aspartic acidto mimic activation by cAMP-dependent protein kinase A (PKA). HumanPDE4B1 contained a corresponding mutation of serine 133 to aspartic acidto also mimic PKA activation. These methods were adapted from Burgin, A.B. et al., “Design of Phosphodiesterase Type 4D (PDE4D) AllostericModulators for Cognition with Improved Safety,” Nature Biotechnology 28,63-70 (2010).

Results are shown below in Table 1, in which + indicates <1 μM and −indicates >1 μM. A − does not mean that the compound is undesirable.“ND” indicates no data; these compounds may not yet have been tested. Itis expected that these compounds when tested will be active and willhave utility similar to those that have been tested (“NT”). Also, theasterisk (*) indicates that the PDE4 isoform contains a UCR1 activatingmutation: PDE4B1*=PDE4B1 containing a UCR1 activating mutation S133D.PDE4D7*=PDE4D7 containing a UCR1 activating mutation S54D.

TABLE 1 Activity: Inhibition of PDE4 Ex. PDE4B1* PDE4D7* PDE4D7 No. IC₅₀IC₅₀ IC₅₀ 1 + + ND 2 − − ND 3 + + 4 − − − 5 + + − 6 − + − 7 − − − 8 − NT− 9 + + − 10 + − − 11 − − − 12 − − − 13 ND ND ND 14 ND ND ND 15 + + −16 + + − 17 ND ND ND 18 ND ND ND 19 − − − 20 + + + 21 + + − 22 − NT − 23− NT − 24 − − − 25 − − − 26 − + − 27 + + − 28 − + − 29 + + + 30 + + + 31− NT − 32 − NT − 33 − NT − 34 + − − 35 − − − 36 + − − 37 − − − 38 + + +39 + + − 40 + + + 41 + + + 43 − − − 44 − − NT 45 − + NT 46 + + NT 47 − −NT 48 − + NT 49 − − NT 50 − NT NT 51 + + + 52 + + + 53 − − NT 54 + + NT55 + + NT 56 + + NT 57 + + + 58 + + + 59 − + NT 60 − + NT 61 − + −62 + + + 63 − − NT 64 − − ND 65 + + + 66 − + − 67 + + + 68 + + − 69 − +− 70 − − − 71 + + + 72 − − ND 73 + + ND 74 + + ND 75 + + ND 76 + + ND77 + + ND 78 + + ND 79 + + ND 80 + ND + 81 + ND + 82 + ND + 83 − ND − 84− ND − 85 + ND + 86 ND − 87 − ND − 88 + ND − 89 − ND − 90 − ND − 91 NDND ND 92 − ND − 93 + ND − 94 + ND − 95 − ND ND 96 − ND − 97 − ND − 98,99 − ND − 100 − ND − 101 − ND − 102 − ND − 103 − ND − 104 − ND − 105 −ND − 106 − ND − 107 − ND − 108 + ND + 109 + ND − 110 − ND − 111 + ND −112 + ND − 113 + ND − 114 − ND − 115 + + − 116 + ND − 117 − ND − 118 −ND − 119 + ND − 120 + ND − 121 + ND + 122 + ND − 123 ND ND ND 124 + ND −125 + ND − 126 − ND − 127 − ND − 128 − ND − 129 + ND − 130 + ND − 131 +ND − 132 − ND − 133 − ND − 134 − ND − 135, 136 − ND ND 137 − ND ND 138 +ND − 139 + ND + 140 + ND − 141 − ND − 142 − ND − 143 + ND − 144 + ND −145 + ND + 146 + ND + 147 + ND + 148 + ND − 149 + ND − 150 + ND − 151 −ND − 152 + ND − 153 − ND − 154 − ND − 155 − ND − 156 + ND − 157 − ND −158 − ND − 159 − ND − 160 − ND − 161 + ND − 162 + ND + 163 + ND + 164 −ND − 165 + ND − 166 − ND − 167 + ND − 168 + ND − 169 − ND − 170 − ND −171 + ND + 172 + ND − 173 + ND − 174 − ND − 175 + ND − 176 − ND − 177 −ND − 178 − ND − 179 − ND − 180 − ND − 181 + ND − 182 + ND + 183 − ND −184 − ND − 185 − ND − 186 − ND − 187 − ND − 188 − ND − 189 + ND + 190 +ND + 191 + ND + 192 − ND − 193 + ND − 194 + ND + 195 + ND + 196 − ND −197 − ND − 198 − ND − 199 − ND + 200 − ND − 201 − ND − 202 − ND − 203 −ND − 204 − ND − 205 − ND − 206 + ND + 207 + ND + 208 − ND − 209 − ND −210 − ND − 211 − ND − 212 − − − 213 − − − 214 − + − 215 + + + 216 + ND +217 + ND − 218 − + − 219 + ND − 220 + ND + 221 + ND + 222 + ND + 223 −ND − 224 − ND − 225 − ND − 226 − ND + 227 + ND + 228 + ND + 229 − ND −230 + ND − 231 − ND − 232 − ND − 233 − ND − 234 + + + 235 + + + 236 − ND− 237 − ND − 238 − ND − 239 − ND − 240 + ND − 241 − ND − 242 − ND − 243− ND − 244 − ND − 245 + ND − 246 − ND − 247 + ND − 248 − ND − 249 − ND −250 + ND − 251 − ND − 252 − ND ND 253 − ND − 254 − ND ND 255 − ND −256 + ND − 257 + ND − 258 − ND − 259 − ND − 260 + ND − 261 + ND − 262 −ND − 263 − ND − 264 + ND + 265 + ND + 266 − ND − 267 − ND − 268 + ND +269 + ND + 270 + ND + 271 + ND + 272 + ND + 273 + ND + 274 + ND + 275 +ND + 276 + ND − 277 + ND + 278 + ND + 279 + ND + 280 + ND + 281 + ND +282 + ND − 283 + + + 284 + + + 285 + + + 286 + + + 287 + + + 288 + + +289 − ND − 290 + ND − 291 − ND − 292 + + + 293 + + + 294 + − − 295 + + −296 + − − 297 + − − 298 + + − 299 − ND − 300 + + − 301 + + − 302 + − −303 − − − 304 + ND − 305 + + − 306 + − − 307 + + + 308 + + − 309 + + +310 − − − 311 + − − 312 + + − 313 + + + 314 + + + 315 + + + 316 + + +317 + + −

Table 2 shows the selectivity of certain compounds disclosed herein. InTable 2, + indicates a selectivity of the given ratio of isoformsof >10×, and − indicates a selectivity of ≤10×. A − does not mean thatth compound is undesirable. “ND” indicates no data; these compounds maynot yet have been tested. It is expected that these compounds whentested will be active and will have utility similar to those that havebeen tested. Again, the asterisk (*) indicates that the PDE4 isoformcontains a UCR1 activating mutation: PDE4B1*=PDE4B1 containing a UCR1activating mutation S133D. PDE4D7*=PDE4D7 containing a UCR1 activatingmutation S54D.

TABLE 2 Selectivity PDE4 Isoforms Ex. No. D*/B* B*/D* D/B* D/D* 1 ND −ND ND 2 ND − ND ND 3 ND − ND + 4 ND + ND ND 5 − ND + + 6 ND + ND − 7 ND− ND − 9 + ND + ND 10 + ND + ND 20 − ND ND + 21 − ND ND + 24 − − − − 25− ND − − 26 ND − ND ND 27 − ND − − 28 ND − − − 29 − − − − 30 − − − − 34− ND ND ND 36 − − ND ND 37 − − − − 38 − ND − − 39 − − − − 40 − − − − 41ND ND − ND 43 − − − − 44 − − ND ND 47 − − ND ND 48 ND − ND ND 51 − − + +52 ND + − + 54 − − ND ND 55 − ND ND ND 56 ND − ND ND 57 ND + − + 58 ND +− + 59 ND + ND ND 60 ND − ND ND 61 ND + − + 62 ND − − + 63 ND − ND ND 64− ND ND ND

In Vivo Assays

PDE4 inhibitors may be shown to be effective in an animal model ofdepression (such as forced swimming test) and animal models of memory(such as maze test and novel object recognition test). See Saccomano, N.A. et al., J. Med. Chem. 34, p 291-298, 1991; O'Donnell, J. M. andZhang, H. T., Trends Pharmacol. Sci., 25, p 158-163 (2004; Zhang, H. T.and O'Donnell, J. M, Psychopharmacology, 150, p 311-316, 2000. Sincethese improvements are hypothesized to be caused by activation of thecentral nerve system as a result of increase of the intracellular cAMPlevel, compounds disclosed herein are expected to be effective indiseases that are improved by activation of the central nervous system.Examples of such diseases include depression, anxiety, degradation oflearning and memory ability, Alzheimer's disease, arterioscleroticdementia, Parkinson's disease, Huntington's disease and late motordisorders.

Depression

The forced-swim test (FST) is the most widely used test ofantidepressant drug action. In the FST, a rat is placed in aninescapable cylinder of water. (See Krishnan V and Nestler E J, “Animalmodels of depression: molecular perspectives,” Current topics inbehavioral neurosciences 2011; 7:121-47; and Bergner C L et al., “Mousemodels for studying depression-like states and antidepressant drugs,”Methods Mol Biol 2010; 602:267-82.) This causes stress to the animal andfollowing an initial period of swimming and climbing, the rat eventuallydisplays a floating or immobile posture. The rat is removed from thewater after 15 minutes. Immobility has been interpreted as an expressionof behavioral despair or entrapment and is reversed by the single doseadministration of almost all available antidepressants.

Intact, adult male or female rats are used for the FST. Either outbredor inbred strains of rats may be used for the study. The rats are grouphoused and allowed to acclimate for 7 days after arrival. All rats willbe housed on standard bedding, kept under a reversed 12:12 hr light:dark(lights on ˜6 pm:6 am), and will receive food and water ad lib.

Comparison is made between a group of 10 rats that is dosed with vehicleonly versus groups of 10 rats that are dosed with varying amounts of thetest compound. Typically, test compounds are dosed at 0.1, 0.3, 1, 3,and 10 mg/kg by oral gavage. The dosing volume will be 10 ml/Kg for PO.The vehicle for dosing will be chosen based on the solubility of thecompound. For oral dosing, the compound may be dosed in solution or maybe dosed in suspension depending upon solubility. PO dosing is performedby oral gavage while the rat is restrained by hand using a flexible tubeappropriate for rat.

For the FST, rats are placed in a cylindrical 5 gallon tank so theanimals can swim or float without touching the bottom with their tails.The test is recorded via video camera for analysis offline or scored inreal time by an observer. Behavior is scored by categorizing behavior asactive escape (swimming, climbing), passive (floating immobile) orneutral (quiet paddling or grooming behaviors). For each rat, onset tothe first 5 second bout of immobility, the number of bouts ofimmobility, and total time spent immobile is recorded. Immobility may becompared during the first 5 min of the FST or during the last 5 min ofthe FST. Comparison of data between groups is by ANOVA.

Compounds disclosed herein are expected to demonstrate activity in themodels disclosed above, and to have utility in the treatment of diseasesdisclosed herein, including disorders of the central nervous system,psychological disorders, and disorders of cognition.

Cognition and Memory

PDE4 inhibitors, for example PDE4D inhibitors, are expected to haveutility as memory enhancers and cognitive adjuvants. One test for theefficacy of compounds disclosed herein may be carried out as describedby Li, Y F et al., “Phosphodiesterase-4D knock-out and RNAinterference-mediated knock-down enhance memory and increase hippocampalneurogenesis via increased cAMP signaling,” J Neurosci. 2011 Jan. 5;31(1): 172-183.

Compounds disclosed herein are expected to demonstrate activity in themodels disclosed above, and to have utility in the treatment of diseasesdisclosed herein, including disorders of the central nervous system,psychological disorders, and disorders of cognition.

Solubility Protocol

To measure compound solubility in aqueous buffer, about 5 mg of acompound may be mixed with 500 μL of pH 7.4, 0.1 M sodium phosphatebuffer. The mixture is adjusted to the original pH of 7.4 and then mixedovernight or longer via rotary mixing. The sample is checked for pH andthen filtered through a 0.45 μm filter. If the pH drifted away, thesample is adjusted to its original pH and mixed for at least 15 minutesbefore filtration. The filtrate is analyzed using HPLC. Generally,solubility ≥1 mg/mL is considered to be better than solubility of <1mg/mL, as it is generally easier to formulate for oral delivery. Certaincompounds disclosed herein are expected to have solubility of ≥1 mg/mL.However, ideal solubility may vary; for example, an aqueous formulationmay benefit from an even higher solubility. Conversely, a formulationcontaining hydrophilic carriers and one or more surfactants may be usedto deliver a compound of low aqueous solubility.

Stability Protocol

To provide a measure of compound stability, about 3 mg of a compound maybe dissolved in 3 mL of acetonitrile/water mixture (50/50). 100 μL ofthe stock solution is added to 20 mL each of 0.025 M pH 5.0 sodiumacetate buffer (A5.0), 0.025 M pH 5.0 citrate buffer (C5.0) and 0.025 MpH 7.4 sodium phosphate buffer (P7.4). A two mL aliquot of each solutionis kept in a glass vial equipped a cap lined with Teflon. Two vialscontaining the solution may be stored at 4° C. or −20° C. as control.Other aliquots may be stressed at RT, 45° C. or 75° C. for specifiedtime check points, e.g. 1 day, 1 week, 2 weeks, 4 weeks, 8 weeks, or 12weeks. The stressed samples in duplicate are assayed against the controlusing HPLC. The results are reported in % degradation. Preliminary shelflife (T90) is estimated assuming the rate of chemical degradation isdouble when the temperature is up 10° C.

It is expected that certain compounds disclosed herein, when tested,will be sufficiently shelf-stable.

From the foregoing description, one skilled in the art can easilyascertain the essential characteristics of this invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions.

1-50. (canceled)
 51. A compound of structural Formula XI:

or a salt thereof, wherein: Y is chosen from O, NH, NR₂, CH₂, C(R₂)₂,and S(O)_(n); X is chosen from CH and N; n is an integer chosen from 0,1 or 2; each R₂ is independently chosen from hydrogen and lower alkyl;R₃ is chosen from methyl, ethyl, trifluoromethyl, and cyclopropyl; R₄ ischosen from hydrogen and ethyl; or R₃ and R₄, together with the atoms towhich they are attached, join to form a 5 to 6 membered cycloalkyl orheterocycloalkyl of the form:

V₁ is chosen from CH₂, N, O, SO₂, and S; V₂ is chosen from a bond, N, Oand CH₂; R₅ is either benzoxaborole, or is chosen from phenyl andpyridinyl, either of which is para-substituted with a substituent of theform R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is optionally substituted with asubstituent R₁₃; R₈ is chosen from a bond and lower alkyl; R₉ is chosenfrom halogen, lower alkyl, lower haloalkyl, lower hydroxyalkyl, loweralkoxy, lower haloalkoxy, cyano, —C(O)N—, S(O)₂—, B(OH)₂, 5-6 memberedmonocyclic heterocycloalkyl, and 5-6 membered monocyclic heteroaryl;(R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, lowerhydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O lower alkyl;R₁₃ is chosen from halogen, hydroxy, lower alkyl, trifluoromethyl, loweralkoxy, trifluoromethoxy, NH₂, and cyano; R₆ is chosen from3-chlorophenyl, 5-chloro-2-thienyl, cyclopentyl optionally substitutedwith one or two R₁₄, and cyclopentoxy optionally substituted with one ortwo R₁₄; and each R₁₄ is independently chosen from halogen, hydroxy,lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, andcyano.
 52. The compound as recited in claim 51, of structural FormulaXII:

or a salt thereof, wherein: Y is chosen from O, NH, and CH₂; X is chosenfrom CH and N; V₁ is chosen from CH₂, N, O, SO₂, and S; V₂ is chosenfrom a bond, N, O and CH₂; R₅ is either benzoxaborole, or is chosen fromphenyl and pyridinyl, either of which is para-substituted with asubstituent of the form R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is optionallysubstituted with a substituent R₁₃; R₈ is chosen from a bond and loweralkyl; R₉ is chosen from halogen, lower alkyl, lower haloalkyl, lowerhydroxyalkyl, lower alkoxy, lower haloalkoxy, cyano, —C(O)N—, S(O)₂—,B(OH)₂, 5-6 membered monocyclic heterocycloalkyl, and 5-6 memberedmonocyclic heteroaryl; (R₁₀)_(a) and (R₁₀)_(b) are each independentlychosen from null, hydrogen, halogen, trifluoromethyl, trifluoromethoxy,hydroxyl, lower hydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)Olower alkyl; R₁₃ is chosen from halogen, hydroxy, lower alkyl,trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, and cyano; R₆ ischosen from 3-chlorophenyl, 5-chloro-2-thienyl, cyclopentyl optionallysubstituted with one or two R₁₄, and cyclopentoxy optionally substitutedwith one or two R₁₄; and each R₁₄ is independently chosen from halogen,hydroxy, lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy,NH₂, and cyano.
 53. The compound as recited in claim 52, having any oneof Formulas XIIa, XIIb, XIIc, XIId, XIIe, and XIIf:

or a salt thereof, wherein: Y is chosen from O, NH, and CH₂; X is chosenfrom CH and N; R₅ is either benzoxaborole, or is chosen from phenyl andpyridinyl, either of which is para-substituted with a substituent of theform R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is optionally substituted with asubstituent R₁₃; R₈ is chosen from a bond and lower alkyl; R₉ is chosenfrom halogen, lower alkyl, lower haloalkyl, lower hydroxyalkyl, loweralkoxy, lower haloalkoxy, cyano, —C(O)N—, S(O)₂—, B(OH)₂, 5-6 memberedmonocyclic heterocycloalkyl, and 5-6 membered monocyclic heteroaryl;(R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, lowerhydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O lower alkyl;R₁₃ is chosen from halogen, hydroxy, lower alkyl, trifluoromethyl, loweralkoxy, trifluoromethoxy, NH₂, and cyano; R₆ is chosen from3-chlorophenyl, 5-chloro-2-thienyl, cyclopentyl optionally substitutedwith one or two R₁₄, and cyclopentoxy optionally substituted with one ortwo R₁₄; and each R₁₄ is independently chosen from halogen, hydroxy,lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, andcyano.
 54. A compound of any one of structural Formulas XIII, XIV, XV,and XVI:

or a salt thereof, wherein: Y is chosen from O, NH, and CH₂; X is chosenfrom CH and N; R₅ is either benzoxaborole, or is chosen from phenyl andpyridinyl, either of which is para-substituted with a substituent of theform R₈—R₉—(R₁₀)_(a)(R₁₀)_(b), and is optionally substituted with asubstituent R₁₃; R₈ is chosen from a bond and lower alkyl; R₉ is chosenfrom halogen, lower alkyl, lower haloalkyl, lower hydroxyalkyl, loweralkoxy, lower haloalkoxy, cyano, —C(O)N—, S(O)₂—, B(OH)₂, 5-6 memberedmonocyclic heterocycloalkyl, and 5-6 membered monocyclic heteroaryl;(R₁₀)_(a) and (R₁₀)_(b) are each independently chosen from null,hydrogen, halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, lowerhydroxyalkyl, cyano, oxo, lower alkyl, C(O)OH, and C(O)O lower alkyl;R₁₃ is chosen from halogen, hydroxy, lower alkyl, trifluoromethyl, loweralkoxy, trifluoromethoxy, NH₂, and cyano; R₆ is chosen from3-chlorophenyl, 5-chloro-2-thienyl, cyclopentyl optionally substitutedwith one or two R₁₄, and cyclopentoxy optionally substituted with one ortwo R₁₄; and each R₁₄ is independently chosen from halogen, hydroxy,lower alkyl, trifluoromethyl, lower alkoxy, trifluoromethoxy, NH₂, andcyano.
 55. A pharmaceutical composition comprising a compound as recitedin claim 51, together with a pharmaceutically acceptable carrier.
 56. Amethod of treatment of a PDE4-mediated disease in a subject comprisingthe administration of a therapeutically effective amount of a compoundas recited in claim
 51. 57. The method as recited in claim 56 whereinthe PDE4 is PDE4B.
 58. The method as recited in claim 57 wherein thePDE4B-mediated disease is chosen from depression, depression secondaryto illness, Huntington's disease, Alzheimer's Disease, cognitiveimpairment, and schizophrenia.
 59. The method as recited in claim 56wherein the PDE4 is PDE4D.
 60. A method of treatment of disease in asubject comprising the administration of a therapeutically effectiveamount of a compound as recited in claim 51, wherein the disease ischosen from depression, depression secondary to illness, Huntington'sdisease, Alzheimer's Disease, cognitive impairment, and schizophrenia.61. A method of modulation of a PDE4-mediated function in a subjectcomprising the administration of a therapeutically effective amount of acompound as recited in claim 51, wherein: the PDE4 is PDE4D; themodulation is enhancement; and the function is cognition.
 62. A methodfor achieving an effect in a patient comprising the administration of atherapeutically effective amount of a compound as recited in claim 51 toa patient, wherein the effect is cognition enhancement.
 63. A method forachieving an effect in a patient comprising the administration of atherapeutically effective amount of a compound as recited in claim 51 toa patient, wherein the effect is cognition enhancement.
 64. A method ofinhibiting PDE4 comprising contacting PDE4 with a compound as recited inclaim 51.